U.S. patent number 11,046,710 [Application Number 16/472,109] was granted by the patent office on 2021-06-29 for sulfonamide compounds.
This patent grant is currently assigned to Daiichi Sankyo Company, Limited, Sanford Burnham Prebys Medical Discovery Institute. The grantee listed for this patent is DAIICHI SANKYO COMPANY, LIMITED, SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE. Invention is credited to Masaharu Inui, Masanori Izumi, Masamichi Kishida, Yasunobu Kurosaki, Shojiro Miyazaki, Anthony Pinkerton, Kaori Soma, Yuko Yamamoto.
United States Patent |
11,046,710 |
Miyazaki , et al. |
June 29, 2021 |
Sulfonamide compounds
Abstract
The present invention relates to a compound or a
pharmacologically acceptable salt thereof having excellent tissue
non-specific alkaline phosphatase inhibitory activity. The present
invention provides a compound represented by the formula (I) or a
pharmacologically acceptable salt thereof. ##STR00001##
Inventors: |
Miyazaki; Shojiro (Tokyo,
JP), Inui; Masaharu (Tokyo, JP), Kurosaki;
Yasunobu (Tokyo, JP), Yamamoto; Yuko (Tokyo,
JP), Izumi; Masanori (Tokyo, JP), Soma;
Kaori (Tokyo, JP), Pinkerton; Anthony (La Jolla,
CA), Kishida; Masamichi (Tokyo, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
DAIICHI SANKYO COMPANY, LIMITED
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE |
Tokyo
La Jolla |
N/A
CA |
JP
US |
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Assignee: |
Daiichi Sankyo Company, Limited
(Toyko, JP)
Sanford Burnham Prebys Medical Discovery Institute (LaJolla,
CA)
|
Family
ID: |
1000005642908 |
Appl.
No.: |
16/472,109 |
Filed: |
December 22, 2017 |
PCT
Filed: |
December 22, 2017 |
PCT No.: |
PCT/US2017/068314 |
371(c)(1),(2),(4) Date: |
June 20, 2019 |
PCT
Pub. No.: |
WO2018/119444 |
PCT
Pub. Date: |
June 28, 2018 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20200087321 A1 |
Mar 19, 2020 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62438722 |
Dec 23, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
498/14 (20130101) |
Current International
Class: |
C07D
498/14 (20060101); A61K 31/553 (20060101); A61P
19/00 (20060101); A61P 17/00 (20060101) |
Foreign Patent Documents
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Feb 1999 |
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CN |
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Feb 2015 |
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CN |
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106132954 |
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Nov 2016 |
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CN |
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97/17344 |
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May 1997 |
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WO |
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2009/017863 |
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Feb 2009 |
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WO |
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WO |
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WO |
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WO |
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WO |
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Other References
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.
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|
Primary Examiner: Kifle; Bruck
Attorney, Agent or Firm: Christensen O'Connor Johnson
Kindness PLLC
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Application No.
62/438,722, filed Dec. 23, 2016, expressly incorporated herein by
reference in its entirety.
Claims
What is claimed is:
1. A compound represented by formula (I): ##STR00055## wherein X
represents --CH.dbd., --C(--R.sup.1).circleincircle., or --N.dbd.,
each substituent R.sup.1 may be the same or different and each
represents a C1-6 alkyl group wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B, a C1-6 alkoxy
group wherein the alkoxy group is optionally substituted by one to
three groups, which may be the same or different, selected from
substituent group A.sup.B, a halogeno group, a C6-10 aryl group
wherein the aryl group is optionally substituted by one or two
groups, which may be the same or different, selected from
substituent group A.sup.C, a 3- to 10-membered heterocyclyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur wherein the
heterocyclyl group is optionally substituted by one or two groups,
which may be the same or different, selected from substituent group
A.sup.C, a hydroxy group, an amino group wherein the amino group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups each optionally substituted by one
to three groups, which may be the same or different, selected from
substituent group A.sup.D, a carboxyl group, a C1-6 alkoxycarbonyl
group wherein the alkoxycarbonyl group is optionally substituted by
one to three groups, which may be the same or different, selected
from substituent group A.sup.D, an aminocarbonyl group wherein the
aminocarbonyl group is optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups each
optionally substituted by one to three groups, which may be the
same or different, selected from substituent group A.sup.D, or a
cyano group, m represents an integer selected from 1 to 4, A
represents one of formula (IIa) to (IIh) ##STR00056## ##STR00057##
Y represents --CH.sub.2--, --CH(--R.sup.8g)--, --O--, or
--N(--R.sup.8g)--, Z represents --CH.sub.2--, --CH(--R.sup.8h)--,
--O--, or --N(--R.sup.8h)--, R.sup.2 and R.sup.3 are the same or
different and each represent a hydrogen atom; a C1-6 alkyl group
wherein the alkyl group is optionally substituted by one to three
groups, which may be the same or different, selected from the
following substituents: a hydroxy group, a C1-6 alkoxy group
optionally substituted by one group selected from substituent group
A.sup.E, a C3-8 cycloalkyl group optionally substituted by one
group selected from substituent group A.sup.F, a C6-10 aryl group
optionally substituted by one or two groups selected from
substituent group A.sup.F, a 3- to 10-membered heterocyclyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur and
optionally substituted by one or two groups selected from
substituent group A.sup.F, a carboxyl group, a C1-6 alkylcarbonyl
group, a C1-6 alkoxycarbonyl group, an amino group optionally
substituted by one or two groups, which may be the same or
different C1-6 alkyl groups, an aminocarbonyl group optionally
substituted by one or two groups, which may be the same or
different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur, an aminocarbonyloxy group optionally substituted by one or
two groups, which may be the same or different C1-6 alkyl groups, a
4- to 7-membered saturated heterocyclylcarbonyloxy group containing
one or two heteroatoms, which may be the same or different,
selected from nitrogen, oxygen, and sulfur, a halogeno group, and a
cyano group; a C6-10 aryl group wherein the aryl group is
optionally substituted by one or two groups, which may be the same
or different, selected from the following substituents: a hydroxy
group, a C1-6 alkoxy group optionally substituted by one to three
groups, which may be the same or different halogeno groups, a C1-6
alkyl group optionally substituted by one group selected from
substituent group A.sup.G, a C3-8 cycloalkyl group optionally
substituted by one group selected from substituent group A.sup.G, a
C6-10 aryl group optionally substituted by one group selected from
substituent group A.sup.G, a 3- to 10-membered heterocyclyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur and
optionally substituted by one group selected from substituent group
A.sup.G, an amino group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups, a
carboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl
group, an aminocarbonyl group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups, a 4-
to 7-membered saturated heterocyclylcarbonyl group containing one
or two heteroatoms, which may be the same or different, selected
from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyloxy group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur, a halogeno group, and a cyano group; a 3- to
10-membered heterocyclyl group containing one to four heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur wherein the heterocyclyl group is optionally substituted
by one or two groups, which may be the same or different, selected
from the following substituents: a hydroxy group, a C1-6 alkoxy
group optionally substituted by one to three groups, which may be
the same or different halogeno groups, a C1-6 alkyl group
optionally substituted by one group selected from substituent group
A.sup.G, a C3-8 cycloalkyl group optionally substituted by one
group selected from substituent group A.sup.G, a C6-10 aryl group
optionally substituted by one group selected from substituent group
A.sup.G, a 3- to 10-membered heterocyclyl group containing one to
four heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur, and optionally substituted by one
group selected from substituent group A.sup.G, an amino group
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups, a carboxyl group, a C1-6
alkylcarbonyl group, a C1-6 alkoxycarbonyl group, an aminocarbonyl
group optionally substituted by one or two groups, which may be the
same or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur, an aminocarbonyloxy group optionally substituted by one or
two groups, which may be the same or different C1-6 alkyl groups, a
4- to 7-membered saturated heterocyclylcarbonyloxy group containing
one or two heteroatoms, which may be the same or different,
selected from nitrogen, oxygen, and sulfur, a halogeno group, and a
cyano group; a C1-6 alkylcarbonyl group wherein the alkylcarbonyl
group is optionally substituted by one to three groups, which may
be the same or different, selected from substituent group A.sup.H;
a C6-10 arylcarbonyl group wherein the arylcarbonyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.H and a C1-6
halogenoalkyl group; a 3- to 10-membered heterocyclylcarbonyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur wherein the
heterocyclylcarbonyl group is optionally substituted by one or two
groups, which may be the same or different, selected from
substituent group A.sup.H and a C1-6 halogenoalkyl group; a
carboxyl group; a C1-6 alkoxycarbonyl group wherein the
alkoxycarbonyl group is optionally substituted by one to three
groups, which may be the same or different, selected from
substituent group A.sup.J; an aminocarbonyl group wherein the
aminocarbonyl group is optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups each
optionally substituted by one to three groups, which may be the
same or different, selected from substituent group A.sup.J; a C6-10
arylaminocarbonyl group wherein the arylaminocarbonyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.H and a C1-6
halogenoalkyl group; a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur wherein the heterocyclylcarbonyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.J; or a 3- to
10-membered heterocyclylaminocarbonyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur wherein the heterocyclylaminocarbonyl
group is optionally substituted by one or two groups, which may be
the same or different, selected from substituent group A.sup.H and
a C1-6 halogenoalkyl group, or the C1-6 alkyl groups of R.sup.2 and
R.sup.3 are optionally bonded to each other to form a 3- to
6-membered saturated carbocyclic ring or to form a 4- to 6-membered
saturated heterocyclic ring via one nitrogen or oxygen atom wherein
one nitrogen atom in the 4- to 6-membered saturated heterocyclic
ring is optionally replaced with a hydrogen atom, a C1-6 alkyl
group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl group,
R.sup.4 and R.sup.5 are the same or different and each represent a
hydrogen atom, a C1-6 alkyl group wherein the alkyl group is
optionally substituted by one to three groups, which may be the
same or different, selected from substituent group A.sup.C, a C6-10
aryl group wherein the aryl group is optionally substituted by one
or two groups, which may be the same or different, selected from
substituent group A.sup.C, or a 3- to 10-membered heterocyclyl
group containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur wherein the
heterocyclyl group is optionally substituted by one or two groups,
which may be the same or different, selected from substituent group
A.sup.C, R.sup.6 represents a hydrogen atom, a C1-6 alkyl group
wherein R.sup.6 is a carbon substituent of the pyridinyl ring, not
a nitrogen substituent, or a hydroxy group, each substituent
R.sup.7a-R.sup.7e may be the same or different and each represents
a hydrogen atom, a C1-6 alkyl group wherein the alkyl group is
optionally substituted by one to three groups, which may be the
same or different, selected from substituent group A.sup.B, a C6-10
aryl group wherein the aryl group is optionally substituted by one
or two groups, which may be the same or different, selected from
substituent group A.sup.B, a 3- to 10-membered heterocyclyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur wherein the
heterocyclyl group is optionally substituted by one or two groups,
which may be the same or different, selected from substituent group
A.sup.B, or a hydroxy group, each substituent R.sup.8f-R.sup.8h may
be the same or different and each represents a hydrogen atom, a
C1-6 alkyl group wherein the alkyl group is optionally substituted
by one to three groups, which may be the same or different,
selected from substituent group A.sup.B, a C3-8 cycloalkyl group
wherein the cycloalkyl group is optionally substituted by one group
selected from substituent group A.sup.B, a C6-10 aryl group wherein
the aryl group is optionally substituted by one or two groups,
which may be the same or different, selected from substituent group
A.sup.K, a 3- to 10-membered heterocyclyl group containing one to
four heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.K, a hydroxy
group, a C1-6 alkoxy group wherein the alkoxy group is optionally
substituted by one group selected from substituent group A.sup.D, a
C3-8 cycloalkyloxy group wherein the cycloalkyloxy group is
optionally substituted by one group selected from substituent group
A.sup.D, a C6-10 aryloxy group wherein the a C6-10 aryloxy group is
optionally substituted by one or two groups selected from
substituent group A.sup.D, a carboxyl group, a C1-6 alkylcarbonyl
group wherein the alkylcarbonyl group is optionally substituted by
one or two groups selected from substituent group A.sup.B, a C1-6
alkoxycarbonyl group wherein the alkoxycarbonyl group is optionally
substituted by one or two groups selected from substituent group
A.sup.D, an aminocarbonyl group wherein the aminocarbonyl group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur, a C1-6 alkylcarbonyloxy group wherein the alkylcarbonyloxy
group is optionally substituted by one to three halogeno groups, an
aminocarbonyloxy group wherein the aminocarbonyloxy group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyloxy group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur, an amino group wherein the amino group is optionally
substituted by one or two groups, which may be the same or
different, selected from the following substituents: a C1-6 alkyl
group optionally substituted by one to three groups, which may be
the same or different, selected from substituent group A.sup.C, a
C3-8 cycloalkyl group optionally substituted by one group selected
from substituent group A.sup.C, a C6-10 aryl group optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.K, a 3- to
10-membered heterocyclyl group containing one to four heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur optionally substituted by one or two groups, which may
be the same or different, selected from substituent group A.sup.K,
a C1-6 alkoxycarbonyl group optionally substituted by one or two
groups, selected from substituent group A.sup.D, and an
aminocarbonyl group optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups, a halogeno
group, or a cyano group, n represents an integer selected from 1 to
4, and the substituent groups represent A.sup.B: a hydroxy group, a
C1-6 alkoxy group, a C3-8 cycloalkyl group, a C6-10 aryl group, a
3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur, a carboxyl group, a C1-6
alkoxycarbonyl group, an aminocarbonyl group wherein the
aminocarbonyl group is optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups, an amino
group wherein the amino group is optionally substituted by one or
two groups, which may be the same or different C1-6 alkyl groups, a
halogeno group, and a cyano group; A.sup.C: a hydroxy group, a C1-6
alkoxy group, an amino group wherein the amino group is optionally
substituted by one or two groups, which may be the same or
different C1-6 alkyl groups, a halogeno group, and a cyano group;
A.sup.D: a C1-6 alkyl group, a C1-6 alkoxy group, a carboxyl group,
a C3-8 cycloalkyl group, a C6-10 aryl group, a 3- to 10-membered
heterocyclyl group containing one to four heteroatoms, which may be
the same or different, selected from nitrogen, oxygen, and sulfur,
a carboxyl group, a C1-6 alkoxycarbonyl group, an aminocarbonyl
group wherein the aminocarbonyl group is optionally substituted by
one or two groups, which may be the same or different C1-6 alkyl
groups, a halogeno group, and a cyano group; A.sup.E: a C6-10 aryl
group, a 3- to 10-membered heterocyclyl group containing one to
four heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur, and a halogeno group; A.sup.F: a
hydroxy group, a C1-6 alkyl group wherein the alkyl group is
optionally substituted by one to three halogeno groups, a C1-6
alkoxy group wherein the alkoxy group is optionally substituted by
one to three halogeno groups, a halogeno group, an amino group, and
a cyano group; A.sup.G: a hydroxy group, a C1-6 alkoxy group, an
amino group, a halogeno group, and a cyano group; A.sup.H: a
hydroxy group, a C1-6 alkoxy group, a C3-8 cycloalkyl group, a
C6-10 aryl group, a 3- to 10-membered heterocyclyl group containing
one to four heteroatoms, which may be the same or different,
selected from nitrogen, oxygen, and sulfur, an amino group wherein
the amino group is optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups, a halogeno
group, and a cyano group; A.sup.J: a C1-6 alkoxy group, a C3-8
cycloalkyl group, a C6-10 aryl group, a 3- to 10-membered
heterocyclyl group containing one to four heteroatoms, which may be
the same or different, selected from nitrogen, oxygen, and sulfur,
a halogeno group, and a cyano group, A.sup.K: a
hydroxy group, a C1-6 alkyl group wherein the alkyl group is
optionally substituted by one to three halogeno groups, a C1-6
alkoxy group wherein the alkoxy group is optionally substituted by
one to three halogeno groups, a carboxyl group, a C1-6
alkoxycarbonyl group, an aminocarbonyl group wherein the
aminocarbonyl group is optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups, an amino
group wherein the amino group is optionally substituted by one or
two groups, which may be the same or different C1-6 alkyl groups, a
halogeno group, and a cyano group; or a pharmacologically
acceptable salt thereof.
2. A compound represented by formula (I): ##STR00058## wherein X
represents --CH.dbd. or --N.dbd., each substituent R.sup.1 may be
the same or different and each represents a C1-6 alkoxy group or a
halogeno group, m represents an integer selected from 1 to 2, A
represents one of formula (IIIa) to (IIId) ##STR00059## R.sup.2 and
R.sup.3 are the same or different and each represents a hydrogen
atom or a C1-6 alkyl group, each substituent R.sup.7a-R.sup.7d may
be the same or different and each represents a hydrogen atom or a
C1-6 alkoxy group; or a pharmacologically acceptable salt
thereof.
3. The compound according to claim 2, wherein A is formula (IIId)
##STR00060## or a pharmacologically acceptable salt thereof.
4. The compound according to claim 2, wherein each substituent
R.sup.1 may be the same or different and each represents an ethoxy
group or a fluoro group; or a pharmacologically acceptable salt
thereof.
5. The compound according to claim 2, wherein R.sup.2 and R.sup.3
are the same or different and each represents a hydrogen atom or a
methyl group; or a pharmacologically acceptable salt thereof.
6. The compound according to claim 2, wherein R.sup.7d is a
hydrogen atom; or a pharmacologically acceptable salt thereof.
7. The compound according to claim 1, wherein the compound is
5-Chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-
-methoxybenzenesulfonamide,
2-ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]benzenesulfonamide,
5-chloro-2-methoxy-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2--
f][1,4]oxazepin-10-yl]pyridine-3-sulfonamide; or a
pharmacologically acceptable salt thereof.
8. The compound according to claim 1, wherein the compound is
5-Chloro-2-methoxy-N-(3-methyl-5,6-dihydropyrido[3,2-j][1,2,4]triazolo[4,-
3-d][1,4]oxazepin-10-yl)benzenesulfonamide,
5-chloro-N-(3-ethyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]ox-
azepin-10-yl)-2-methoxybenzenesulfonamide; or a pharmacologically
acceptable salt thereof.
9. The compound according to claim 1, wherein the compound is
N-(5,6-Dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluoropyridine-3-sulfonamide or a pharmacologically acceptable
salt thereof.
10. The compound according to claim 1, wherein the compound is
N-(5,6-Dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluorobenzenesulfonamide or a pharmacologically acceptable salt
thereof.
11. The compound according to claim 1, wherein the compound is
2-Ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]pyridine-3-sulfonamide or a pharmacologically
acceptable salt thereof.
12. The compound according to claim 1, wherein the compound is
5-Chloro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de or a pharmacologically acceptable salt thereof.
13. The compound according to claim 1, wherein the compound is
5-Chloro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de or a pharmacologically acceptable salt thereof.
14. A compound according to claim 1, wherein the pharmacologically
acceptable salt is sodium salt.
15. A compound according to claim 1, wherein the pharmacologically
acceptable salt is potassium salt.
16. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmacologically acceptable salt thereof, as an
active ingredient, and a pharmaceutically acceptable carrier.
17. A method for the treatment of a disease or condition selected
from the group consisting of ectopic calcification, pseudoxanthoma
elasticum (PXE), generalized arterial calcification of infancy
(GACI), calcification of joints and arteries (CALJA), vascular
calcification in CKD/ESRD, calciphylaxis, ossification of posterior
longitudinal ligaments (OPLL), ossification of yellow ligaments
(OYLL), and aortic stenosis, comprising administering a
therapeutically effective amount of a compound according to claim
1, or a pharmacologically acceptable salt thereof, to a subject in
need thereof.
18. A method according to claim 17, wherein the disease or
condition is pseudoxanthoma elasticum (PXE).
19. A method according to claim 17, wherein the subject is a
human.
20. A compound according to claim 2, wherein the pharmacologically
acceptable salt is sodium salt.
21. A compound according to claim 2, wherein the pharmacologically
acceptable salt is potassium salt.
22. A pharmaceutical composition comprising a compound according to
claim 2, or a pharmacologically acceptable salt thereof, as an
active ingredient, and a pharmaceutically acceptable carrier.
23. A method for the treatment of a disease or condition selected
from the group consisting of ectopic calcification, pseudoxanthoma
elasticum (PXE), generalized arterial calcification of infancy
(GACI), calcification of joints and arteries (CALJA), vascular
calcification in CKD/ESRD, calciphylaxis, ossification of posterior
longitudinal ligaments (OPLL), ossification of yellow ligaments
(OYLL), and aortic stenosis, comprising administering a
therapeutically effective amount of a compound according to claim
2, or a pharmacologically acceptable salt thereof, to a subject in
need thereof.
24. A method according to claim 23, wherein the disease or
condition is pseudoxanthoma elasticum (PXE).
25. A method according to claim 23, wherein the subject is a human.
Description
FIELD OF THE INVENTION
The present invention relates to a novel sulfonamide compound or a
pharmacologically acceptable salt thereof which has excellent
tissue non-specific alkaline phosphatase (hereinafter, referred to
as TNAP) inhibitory activity.
The present invention also relates to a therapeutic agent and/or
prophylactic agent (preferably a therapeutic agent) for
pseudoxanthoma elasticum (PXE), generalized arterial calcification
of infancy (GACI), craniometaphyseal dysplasia (CMD), ossification
of the yellow ligament (OYL), ossification of ligamentum flavum,
arterial calcification due to deficiency of CD73 (ACDC),
calcification of joints and arteries (CALJA), arthrosis deformans,
osteoarthritis, ankylosis of the joint, idiopathic infantile
arterial calcification (IIAC), ankylosing spondylitis (AS), tumoral
calcinosis (TC), progressive osseous heteroplasia (POH), Keutel
syndrome, vascular calcification associated with chronic renal
failure (including glomerulonephritis, IgA nephropathy,
hypertensive nephropathy, and diabetic nephropathy) and secondary
parathyroid hyperplasia, metastatic calcification, calciphylaxis,
calcific tendinitis of the longus colli muscle, fibrodysplasia
ossificans progressiva (FOP), calcific aortic stenosis,
pericarditis calculosa, atherosclerotic vascular calcification,
calcific uremic arteriopathy (CUA), Kawasaki disease, calcification
due to obesity and aging, tibial arterial calcification, bone
metastasis, prosthetic calcification, Paget's disease, idiopathic
basal ganglia calcification (IBGC), heterotopic ossification (HO),
calcific aortic valve disease (aortic valve stenosis), calcific
tendinitis, ossification of the posterior longitudinal ligament
(OPLL) ossification of the anterior longitudinal ligament (OALL),
diffuse idiopathic skeletal hyperostosis (DISH), meniscal
calcification, or peritoneal calcification, comprising the compound
or the pharmacologically acceptable salt thereof as an active
ingredient.
The present invention further relates to a composition for the
treatment or prophylaxis of the aforementioned diseases, comprising
the compound or the pharmacologically acceptable salt thereof as an
active ingredient, use of the compound or the pharmacologically
acceptable salt thereof for manufacturing a pharmaceutical for the
treatment or prophylaxis of the disease, and a method for the
treatment or prophylaxis of the disease, comprising administering a
pharmacologically effective amount of the compound or the
pharmacologically acceptable salt thereof to a mammal (preferably a
human).
DESCRIPTION OF THE RELATED ART
In vivo calcification is strictly regulated by the balance of
activation between osteoblasts and osteoclasts, phosphorus and
calcium concentrations in plasma, and parathyroid hormone or
vitamin D secreted in order to maintain the homeostasis of these
concentrations (Non Patent Literature 1). Ectopic calcification is
found in diseases, for example, pseudoxanthoma elasticum (PXE),
generalized arterial calcification of infancy (GACI),
craniometaphyseal dysplasia (CMD), ossification of the yellow
ligament (OYL), ossification of ligamentum flavum, arterial
calcification due to deficiency of CD73 (ACDC), calcification of
joints and arteries (CALJA), arthrosis deformans, osteoarthritis,
ankylosis of the joint, idiopathic infantile arterial calcification
(IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC),
progressive osseous heteroplasia (POH), Keutel syndrome, vascular
calcification associated with chronic renal failure (including
glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and
diabetic nephropathy) and secondary parathyroid hyperplasia,
metastatic calcification, calciphylaxis, calcific tendinitis of the
longus colli muscle, fibrodysplasia ossificans progressiva (FOP),
calcific aortic stenosis, pericarditis calculosa, atherosclerotic
vascular calcification, calcific uremic arteriopathy (CUA),
Kawasaki disease, calcification due to obesity and aging, tibial
arterial calcification, bone metastasis, prosthetic calcification,
Paget's disease, idiopathic basal ganglia calcification (IBGC),
heterotopic ossification (HO), calcific aortic valve disease
(aortic valve stenosis), calcific tendinitis, ossification of the
posterior longitudinal ligament (OPLL) ossification of the anterior
longitudinal ligament (OALL), diffuse idiopathic skeletal
hyperostosis (DISH), meniscal calcification, and peritoneal
calcification. In these pathological conditions, calcification in
tissues (blood vessels, soft tissues, etc.) that are usually not
calcified is caused by the failure of the regulatory mechanism
mentioned above, and is known to bring about significantly reduced
quality of life (QOL) due to the limitation of activity and an
increased cardiovascular risk (Non Patent Literatures 2 and 3). No
existing therapeutic agent is effective for ectopic calcification.
Thus, there are very high unmet medical needs for this disease (Non
Patent Literature 4).
TNAP, one of alkaline phosphatases, includes membrane-bound and
secretory forms. TNAP is expressed in the bone, the liver, and the
kidney and highly expressed particularly in the matrix vesicles of
chondrocytes and osteoblasts. This enzyme is known to play an
important role in in vivo calcification via the degradation of
pyrophosphate, which is an endogenous anti-calcification factor
(Non Patent Literature 5). A large number of reports show the
increased expression level or elevated activity of TNAP at lesion
sites of ectopic calcification, and ectopic calcification also
occurs in mice which overexpress human TNAP, suggesting the
importance of TNAP for ectopic calcification (Non Patent
Literatures 6 and 7). Thus, the inhibition of TNAP is considered to
elevate pyrophosphate concentrations in blood and in tissues and
suppress ectopic calcification (Non Patent Literature 8).
Some compounds are known to have TNAP inhibitory activity (see
e.g., Patent Literatures 1 and 2 and, Non Patent Literatures 9 to
12). Among them, compounds partially having a common skeleton are
disclosed. Nonetheless, a compound having a 7-membered ring
condensed with a pyridine ring has not yet been disclosed.
PATENT LITERATURE
[Patent Literature 1] International Publication No. WO 2009/017863
(PCT/US2008/063106) [Patent Literature 2] International Publication
No. WO 2013/126608 (U.S. Patent Publication No. 2015-0011551)
NON PATENT LITERATURE
[Non Patent Literature 1] J. Bone Miner Res, 2006, vol. 24, p.
176-181 [Non Patent Literature 2] Clin. Kidery. J., 2014, vol. 7,
p. 167-173 [Non Patent Literature 3] Eur. Heart. J., 2014, vol. 35,
p. 1515-1525. [Non Patent Literature 4] Int. J. Nephrol. Renovasc.
Dis., 2014, vol. 7, p. 161-168 [Non Patent Literature 5] J.
Histochem. Cytochem., 2002, vol. 50, p. 333-340 [Non Patent
Literature 6] J. Am. Soc. Nephrol., 2004, vol. 15, p. 1392-1401
[Non Patent Literature 7] J. Bone Miner Res, 2013, vol. 7, p.
1587-1598 [Non Patent Literature 8] J. Bone Miner Res, 2007, vol.
22, p. 1700-1710 [Non Patent Literature 9] Bioorg. Med. Chem.
Lett., 2009, vol. 19, p. 222-225 [Non Patent Literature 10] J. Med.
Chem., 2009, vol. 52, p. 6919-6925 [Non Patent Literature 11]
Bioorg. Med. Chem., 2013, vol. 21, p. 7981-7987 [Non Patent
Literature 12] J. Bone Miner Res, 2015, vol. 30, p. 824-836
SUMMARY OF THE INVENTION
The present inventors have conducted diligent studies and
consequently found that a compound represented by the formula (I)
mentioned later has excellent TNAP inhibitory activity based on its
specific chemical structure, further has excellent properties in
terms of the physicochemical properties (e.g., stability) of a
pharmaceutical, and serves as a safe and useful pharmaceutical as a
prophylactic or therapeutic agent for a pathological condition or a
disease associated with ectopic calcification. On the basis of
these findings, the present invention has been completed.
Specifically, the compound of the present invention has excellent
properties in terms of TNAP inhibitory activity, solubility, cell
membrane permeability, oral absorbability, concentration in blood,
metabolic stability, tissue penetration, bioavailability
(hereinafter, also referred to as BA), in vitro activity, in vivo
activity, ex vivo activity, quick onset of drug efficacy,
persistence of drug efficacy, physical stability, drug interaction,
safety (e.g., cardiotoxicity or hepatotoxicity), etc., and is
useful as a pharmaceutical [particularly, a pharmaceutical for the
treatment or prophylaxis (preferably treatment) of pseudoxanthoma
elasticum (PXE), generalized arterial calcification of infancy
(GACI), craniometaphyseal dysplasia (CMD), ossification of the
yellow ligament (OYL), ossification of ligamentum flavum, arterial
calcification due to deficiency of CD73 (ACDC), calcification of
joints and arteries (CALJA), arthrosis deformans, osteoarthritis,
ankylosis of the joint, idiopathic infantile arterial calcification
(IIAC), ankylosing spondylitis (AS), tumoral calcinosis (TC),
progressive osseous heteroplasia (POH), Keutel syndrome, vascular
calcification associated with chronic renal failure (including
glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and
diabetic nephropathy) and secondary parathyroid hyperplasia,
metastatic calcification, calciphylaxis, calcific tendinitis of the
longus colli muscle, fibrodysplasia ossificans progressiva (FOP),
calcific aortic stenosis, pericarditis calculosa, atherosclerotic
vascular calcification, calcific uremic arteriopathy (CUA),
Kawasaki disease, calcification due to obesity and aging, tibial
arterial calcification, bone metastasis, prosthetic calcification,
Paget's disease, idiopathic basal ganglia calcification (IBGC),
heterotopic ossification (HO), calcific aortic valve disease
(aortic valve stenosis), calcific tendinitis, ossification of the
posterior longitudinal ligament (OPLL) ossification of the anterior
longitudinal ligament (OALL), diffuse idiopathic skeletal
hyperostosis (DISH), meniscal calcification, or peritoneal
calcification].
The present invention provides:
(1) a compound represented by formula (I):
##STR00002##
wherein
X represents --CH.dbd., --C(--R.sup.1).dbd., or --N.dbd.,
each substituent R.sup.1 may be the same or different and may be
each represent
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B),
a C1-6 alkoxy group (wherein the alkoxy group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B),
a halogeno group,
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.C),
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.C), a hydroxy
group, an amino group (wherein the amino group is optionally
substituted by one or two groups, which may be the same or
different C1-6 alkyl groups each optionally substituted by one to
three groups, which may be the same or different, selected from
substituent group A.sup.D), a carboxyl group, a C1-6 alkoxycarbonyl
group (wherein the alkoxycarbonyl group is optionally substituted
by one to three groups, which may be the same or different,
selected from substituent group A.sup.D), an aminocarbonyl group
(wherein the aminocarbonyl group is optionally substituted by one
or two groups, which may be the same or different C1-6 alkyl groups
each optionally substituted by one to three groups, which may be
the same or different, selected from substituent group A.sup.D), or
a cyano group,
m represents an integer selected from 1 to 4,
A represented by one of formula (IIa) to (IIh)
##STR00003## ##STR00004##
Y represents --CH.sub.2--, --CH(--R.sup.8g)--, --O--, or
--N(--R.sup.8g)--,
Z represents --CH.sub.2--, --CH(--R.sup.8h)--, --O--, or
--N(--R.sup.8h)--,
R.sup.2 and R.sup.3 are the same or different and each
represent
a hydrogen atom,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from the following substituents:
a hydroxy group,
a C1-6 alkoxy group optionally substituted by one group selected
from substituent group A.sup.E,
a C3-8 cycloalkyl group optionally substituted by one group
selected from substituent group A.sup.E,
a C6-10 aryl group optionally substituted by one or two groups
selected from substituent group A.sup.E,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur and optionally substituted by one or
two groups selected from substituent group A.sup.E,
a carboxyl group,
a C1-6 alkylcarbonyl group,
a C1-6 alkoxycarbonyl group, an amino group optionally substituted
by one or two groups, which may be the same or different C1-6 alkyl
groups,
an aminocarbonyl group optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups,
a 4- to 7-membered saturated heterocyclylcarbonyl group containing
one or two heteroatoms, which may be the same or different,
selected from nitrogen, oxygen, and sulfur, an aminocarbonyloxy
group optionally substituted by one or two groups, which may be the
same or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyloxy group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur, a halogeno group, and a cyano group), a C6-10 aryl
group (wherein the aryl group is optionally substituted by one or
two groups, which may be the same or different, selected from the
following substituents: a hydroxy group, a C1-6 alkoxy group
optionally substituted by one to three groups, which may be the
same or different halogeno groups, a C1-6 alkyl group optionally
substituted by one group selected from substituent group A.sup.G, a
C3-8 cycloalkyl group optionally substituted by one group selected
from substituent group A.sup.G, a C6-10 aryl group optionally
substituted by one group selected from substituent group A.sup.G, a
3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur and optionally substituted by one
group selected from substituent group A.sup.G, an amino group
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups, a carboxyl group, a C1-6
alkylcarbonyl group, a C1-6 alkoxycarbonyl group, an aminocarbonyl
group optionally substituted by one or two groups, which may be the
same or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur, an aminocarbonyloxy group optionally substituted by one or
two groups, which may be the same or different C1-6 alkyl groups, a
4- to 7-membered saturated heterocyclylcarbonyloxy group containing
one or two heteroatoms, which may be the same or different,
selected from nitrogen, oxygen, and sulfur, a halogeno group, and a
cyano group), a 3- to 10-membered heterocyclyl group containing one
to four heteroatoms, which may be the same or different, selected
from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group
is optionally substituted by one or two groups, which may be the
same or different, selected from the following substituents: a
hydroxy group, a C1-6 alkoxy group optionally substituted by one to
three groups, which may be the same or different halogeno groups, a
C1-6 alkyl group optionally substituted by one group selected from
substituent group A.sup.G, a C3-8 cycloalkyl group optionally
substituted by one group selected from substituent group A.sup.G, a
C6-10 aryl group optionally substituted by one group selected from
substituent group A.sup.G, a 3- to 10-membered heterocyclyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur, and
optionally substituted by one group selected from substituent group
A.sup.G, an amino group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups, a
carboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl
group, an aminocarbonyl group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups, a 4-
to 7-membered saturated heterocyclylcarbonyl group containing one
or two heteroatoms, which may be the same or different, selected
from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyloxy group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur, a halogeno group, and a cyano group), a C1-6
alkylcarbonyl group (wherein the alkylcarbonyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.H), a C6-10
arylcarbonyl group (wherein the arylcarbonyl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.H and a C1-6
halogenoalkyl group), a 3- to 10-membered heterocyclylcarbonyl
group containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur (wherein the
heterocyclylcarbonyl group is optionally substituted by one or two
groups, which may be the same or different, selected from
substituent group A.sup.H and a C1-6 halogenoalkyl group), a
carboxyl group, a C1-6 alkoxycarbonyl group (wherein the
alkoxycarbonyl group is optionally substituted by one to three
groups, which may be the same or different, selected from
substituent group A.sup.J), an aminocarbonyl group (wherein the
aminocarbonyl group is optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups each
optionally substituted by one to three groups, which may be the
same or different, selected from substituent group A.sup.J), a
C6-10 arylaminocarbonyl group (wherein the arylaminocarbonyl group
is optionally substituted by one or two groups, which may be the
same or different, selected from substituent group A.sup.H and a
C1-6 halogenoalkyl group), a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur (wherein the heterocyclylcarbonyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.J), or a 3- to
10-membered heterocyclylaminocarbonyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclylaminocarbonyl
group is optionally substituted by one or two groups, which may be
the same or different, selected from substituent group A.sup.H and
a C1-6 halogenoalkyl group), or
the C1-6 alkyl groups of R.sup.2 and R.sup.3 are optionally bonded
to each other to form a 3- to 6-membered saturated carbocyclic ring
or to form a 4- to 6-membered saturated heterocyclic ring via one
nitrogen or oxygen atom (wherein one nitrogen atom in the 4- to
6-membered saturated heterocyclic ring is optionally replaced with
a hydrogen atom, a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a
C1-6 alkoxycarbonyl group),
R.sup.4 and R.sup.5 are the same or different and each
represent
a hydrogen atom,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.C),
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.C), or
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.C),
R.sup.6 represents
a hydrogen atom,
a C1-6 alkyl group (R.sup.6 is a carbon substituent of the
pyridinyl ring, not a nitrogen substituent) or
a hydroxy group,
each substituent R.sup.7a-R.sup.7e may be the same or different and
may be each represent
a hydrogen atom,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B),
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.B),
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.B), or a
hydroxy group,
each substituent R.sup.8f-R.sup.8h may be the same or different and
may be each represent
a hydrogen atom,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B),
a C3-8 cycloalkyl group (wherein the cycloalkyl group is optionally
substituted by one group selected from substituent group A),
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.K),
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.K), a hydroxy
group, a C1-6 alkoxy group (wherein the alkoxy group is optionally
substituted by one group selected from substituent group A.sup.D),
a C3-8 cycloalkyloxy group (wherein the cycloalkyloxy group is
optionally substituted by one group selected from substituent group
A.sup.D), a C6-10 aryloxy group (wherein the a C6-10 aryloxy group
is optionally substituted by one or two groups selected from
substituent group A.sup.D), a carboxyl group, a C1-6 alkylcarbonyl
group (wherein the alkylcarbonyl group is optionally substituted by
one or two groups selected from substituent group A.sup.B), a C1-6
alkoxycarbonyl group (wherein the alkylcarbonyl group is optionally
substituted by one or two groups selected from substituent group
A.sup.D), an aminocarbonyl group (wherein the aminocarbonyl group
is optionally substituted by one or two groups, which may be the
same or different C1-6 alkyl groups), a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur, a C1-6 alkylcarbonyloxy group (wherein the alkylcarbonyloxy
group is optionally substituted by one to three halogeno groups),
an aminocarbonyloxy group (wherein the aminocarbonyloxy group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups), a 4- to 7-membered saturated
heterocyclylcarbonyloxy group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur, an amino group (wherein the amino group is optionally
substituted by one or two groups, which may be the same or
different, selected from the following substituents: a C1-6 alkyl
group optionally substituted by one to three groups, which may be
the same or different, selected from substituent group A.sup.C, a
C3-8 cycloalkyl group optionally substituted by one group selected
from substituent group A.sup.C, a C6-10 aryl group optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.K, a 3- to
10-membered heterocyclyl group containing one to four heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur optionally substituted by one or two groups, which may
be the same or different, selected from substituent group A.sup.K,
a C1-6 alkoxycarbonyl group optionally substituted by one or two
groups, selected from substituent group A.sup.D, an aminocarbonyl
group optionally substituted by one or two groups, which may be the
same or different C1-6 alkyl groups), a halogeno group, or a cyano
group
n represents an integer selected from 1 to 4,and
the substituent groups represent
A.sup.B: a hydroxy group,
a C1-6 alkoxy group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
a carboxyl group,
a C1-6 alkoxycarbonyl group,
an aminocarbonyl group (wherein the aminocarbonyl group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups),
an amino group (wherein the amino group is optionally substituted
by one or two groups, which may be the same or different C1-6 alkyl
groups),
a halogeno group, and
a cyano group;
A.sup.C: a hydroxy group,
a C1-6 alkoxy group,
an amino group (wherein the amino group is optionally substituted
by one or two groups, which may be the same or different C1-6 alkyl
groups),
a halogeno group, and
a cyano group;
A.sup.D: a C1-6 alky group,
a C1-6 alkoxy group,
a carboxyl group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
a carboxyl group,
a C1-6 alkoxycarbonyl group,
an aminocarbonyl group (wherein the aminocarbonyl group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups),
a halogeno group, and
a cyano group;
A.sup.E: a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur, and
a halogeno group;
A.sup.F: a hydroxy group,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three halogeno groups),
a C1-6 alkoxy group (wherein the alkoxy group is optionally
substituted by one to three halogeno groups),
a halogeno group, an amino group, and
a cyano group;
A.sup.G: a hydroxy group,
a C1-6 alkoxy group, an amino group,
a halogeno group, and
a cyano group;
A.sup.H: a hydroxy group,
a C1-6 alkoxy group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
an amino group (wherein the amino group is optionally substituted
by one or two groups, which may be the same or different C1-6 alkyl
groups),
a halogeno group, and
a cyano group;
A.sup.J: a C1-6 alkoxy group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
a halogeno group, and
a cyano group,
A.sup.K: a hydroxy group,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three halogeno groups),
a C1-6 alkoxy group (wherein the alkoxy group is optionally
substituted by one to three halogeno groups),
a carboxyl group,
a C1-6 alkoxycarbonyl group,
an aminocarbonyl group (wherein the aminocarbonyl group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups), an amino group (wherein the amino
group is optionally substituted by one or two groups, which may be
the same or different C1-6 alkyl groups), a halogeno group, and a
cyano group; or a pharmacologically acceptable salt thereof; (2) a
compound represented by formula (I):
##STR00005##
wherein
X represents --CH.dbd. or --N.dbd.,
each substituent R.sup.1 may be the same or different and may
represent a C1-6 alkoxy group or a halogeno group,
m represents an integer selected from 1 to 2,
A represented by one of formula (IIIa) to (IIId)
##STR00006##
R.sup.2 and R.sup.3 are the same or different and each represent a
hydrogen atom or a C1-6 alkyl group,
each substituent R.sup.7a-R.sup.7d may be the same or different and
may be each represent a hydrogen atom or a C1-6 alkoxy group;
or a pharmacologically acceptable salt thereof;
(3) the compound according to 2 above, wherein A is formula
(IIId)
##STR00007## or a pharmacologically acceptable salt thereof; (4)
the compound according to 2 or 3 above, wherein each substituent
R.sup.1 may be the same or different and may represent an ethoxy
group or a fluoro group, or a pharmacologically acceptable salt
thereof; (5) the compound according to 2 to 4 above, wherein
R.sup.2 and R.sup.3 are the same or different and each represent a
hydrogen atom or a methyl group, or a pharmacologically acceptable
salt thereof; (6) the compound according to 2 to 5 above, wherein
R.sup.7d is a hydrogen atom, or a pharmacologically acceptable salt
thereof; (7)
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-
-methoxybenzenesulfonamide,
2-ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]benzenesulfonamide,
5-chloro-2-methoxy-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2--
f][1,4]oxazepin-10-yl]pyridine-3-sulfonamide, or a
pharmacologically acceptable salt thereof; (8)
5-chloro-2-methoxy-N-(3-methyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,-
3-d][1,4]oxazepin-10-yl)benzenesulfonamide,
5-chloro-N-(3-ethyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]ox-
azepin-10-yl)-2-methoxybenzenesulfonamide, or a pharmacologically
acceptable salt thereof; (9)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluoropyridine-3-sulfonamide, or a pharmacologically acceptable
salt thereof; (10)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluorobenzenesulfonamide, or a pharmacologically acceptable salt
thereof; (11)
2-ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[-
3,2-f][1,4]oxazepin-10-yl]pyridine-3-sulfonamide, or a
pharmacologically acceptable salt thereof; (12)
5-chloro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de, or a pharmacologically acceptable salt thereof; (13)
5-chloro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de, or a pharmacologically acceptable salt thereof; (14) a compound
according to 1 to 13 above, wherein the pharmacologically
acceptable salt is sodium salt; (15) a compound according to 1 to
13 above, wherein the pharmacologically acceptable salt is
potassium salt; (16) a pharmaceutical composition comprising a
compound according to 1 to 13 above, or a pharmacologically
acceptable salt thereof, as an active ingredient; (17) the
pharmaceutical composition according to 16 above, wherein the
pharmaceutical composition is intended for the treatment or
prophylaxis of ectopic calcification, pseudoxanthoma elasticum
(PXE), generalized arterial calcification of infancy (GACI),
calcification of joints and arteries (CALJA), vascular
calcification in CKD/ESRD, calciphylaxis, ossification of posterior
longitudinal ligaments (OPLL), ossification of yellow ligaments
(OYLL), or aortic stenosis; (18) a TNAP inhibitor comprising a
compound according to 1 to 13 above, or a pharmacologically
acceptable salt thereof, as an active ingredient; (19) use of a
compound according to 1 to 13 above, or a pharmacologically
acceptable salt thereof, for the manufacturing a pharmaceutical
composition; (20) a method for the treatment or prophylaxis of a
disease or condition selected from the group consisting of ectopic
calcification, pseudoxanthoma elasticum (PXE), generalized arterial
calcification of infancy (GACI), calcification of joints and
arteries (CALJA), vascular calcification in CKD/ESRD,
calciphylaxis, ossification of posterior longitudinal ligaments
(OPLL), ossification of yellow ligaments (OYLL), and aortic
stenosis, comprising administering a therapeutically effective
amount of a compound according to 1 to 13 above, or a
pharmacologically acceptable salt thereof, to a subject in need
thereof; (21) a method according to 20 above, wherein the disease
or condition is pseudoxanthoma elasticum (PXE); (22) a method for
inhibiting TNAP in a subject, comprising administering an effective
amount of a compound according to 1 to 13 above, or a
pharmacologically acceptable salt thereof, to the subject; (23) a
method according to 20 to 22 above, wherein the subject is a human;
(24) a compound according to 1 to 13 above, or a pharmacologically
acceptable salt thereof, for use in the treatment of disease or
condition selected from the group consisting of ectopic
calcification, pseudoxanthoma elasticum (PXE), generalized arterial
calcification of infancy (GACI), calcification of joints and
arteries (CALJA), vascular calcification in CKD/ESRD,
calciphylaxis, ossification of posterior longitudinal ligaments
(OPLL), ossification of yellow ligaments (OYLL), and aortic
stenosis; (25) a compound according to 1 to 13 above, or a
pharmacologically acceptable salt thereof, for use in the treatment
of pseudoxanthoma elastic (PXE); and (26) a compound represented by
formula (I):
##STR00008##
wherein
X represents --CH.dbd., --C(--R.sup.1).dbd., or --N.dbd.,
each substituent R.sup.1 may be the same or different and may be
each represent
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B),
a C1-6 alkoxy group (wherein the alkoxy group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B),
a halogeno group,
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.C),
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.C), a hydroxy
group, an amino group (wherein the amino group is optionally
substituted by one or two groups, which may be the same or
different C1-6 alkyl groups each optionally substituted by one to
three groups, which may be the same or different, selected from
substituent group A.sup.D), a carboxyl group, a C1-6 alkoxycarbonyl
group (wherein the alkoxycarbonyl group is optionally substituted
by one to three groups, which may be the same or different,
selected from substituent group A.sup.D), an aminocarbonyl group
(wherein the aminocarbonyl group is optionally substituted by one
or two groups, which may be the same or different C1-6 alkyl groups
each optionally substituted by one to three groups, which may be
the same or different, selected from substituent group A.sup.D), or
a cyano group,
m represents an integer selected from 1 to 4,
A represented by one of formula (IIa) to (IIe)
##STR00009##
R.sup.2 and R.sup.3 are the same or different and each
represent
a hydrogen atom,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from the following substituents:
a hydroxy group,
a C1-6 alkoxy group optionally substituted by one group selected
from substituent group A.sup.E,
a C3-8 cycloalkyl group optionally substituted by one group
selected from substituent group A.sup.F,
a C6-10 aryl group optionally substituted by one or two groups
selected from substituent group A.sup.F,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur and optionally substituted by one or
two groups selected from substituent group A.sup.F,
a carboxyl group,
a C1-6 alkylcarbonyl group,
a C1-6 alkoxycarbonyl group,
an amino group optionally substituted by one or two groups, which
may be the same or different C1-6 alkyl groups,
an aminocarbonyl group optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups,
a 4- to 7-membered saturated heterocyclylcarbonyl group containing
one or two heteroatoms, which may be the same or different,
selected from nitrogen, oxygen, and sulfur,
an aminocarbonyloxy group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups,
a 4- to 7-membered saturated heterocyclylcarbonyloxy group
containing one or two heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur,
a halogeno group, and
a cyano group),
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from the following substituents:
a hydroxy group,
a C1-6 alkoxy group optionally substituted by one to three groups,
which may be the same or different halogeno groups,
a C1-6 alkyl group optionally substituted by one group selected
from substituent group A.sup.G,
a C3-8 cycloalkyl group optionally substituted by one group
selected from substituent group A.sup.G,
a C6-10 aryl group optionally substituted by one group selected
from substituent group A.sup.G,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur and optionally substituted by one
group selected from substituent group A.sup.G,
an amino group optionally substituted by one or two groups, which
may be the same or different C1-6 alkyl groups,
a carboxyl group,
a C1-6 alkylcarbonyl group,
a C1-6 alkoxycarbonyl group,
an aminocarbonyl group optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups,
a 4- to 7-membered saturated heterocyclylcarbonyl group containing
one or two heteroatoms, which may be the same or different,
selected from nitrogen, oxygen, and sulfur,
an aminocarbonyloxy group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups,
a 4- to 7-membered saturated heterocyclylcarbonyloxy group
containing one or two heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur,
a halogeno group, and
a cyano group),
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from the following substituents: a hydroxy
group, a C1-6 alkoxy group optionally substituted by one to three
groups, which may be the same or different halogeno groups, a C1-6
alkyl group optionally substituted by one group selected from
substituent group A.sup.G, a C3-8 cycloalkyl group optionally
substituted by one group selected from substituent group A.sup.G, a
C6-10 aryl group optionally substituted by one group selected from
substituent group A.sup.G, a 3- to 10-membered heterocyclyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur, and
optionally substituted by one group selected from substituent group
A.sup.G, an amino group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups, a
carboxyl group, a C1-6 alkylcarbonyl group, a C1-6 alkoxycarbonyl
group, an aminocarbonyl group optionally substituted by one or two
groups, which may be the same or different C1-6 alkyl groups, a 4-
to 7-membered saturated heterocyclylcarbonyl group containing one
or two heteroatoms, which may be the same or different, selected
from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups, a 4- to 7-membered saturated
heterocyclylcarbonyloxy group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur, a halogeno group, and a cyano group), a C1-6
alkylcarbonyl group (wherein the alkylcarbonyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.H), a C6-10
arylcarbonyl group (wherein the arylcarbonyl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.H and a C1-6
halogenoalkyl group), a 3- to 10-membered heterocyclylcarbonyl
group containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur (wherein the
heterocyclylcarbonyl group is optionally substituted by one or two
groups, which may be the same or different, selected from
substituent group A.sup.H and a C1-6 halogenoalkyl group), a
carboxyl group, a C1-6 alkoxycarbonyl group (wherein the
alkoxycarbonyl group is optionally substituted by one to three
groups, which may be the same or different, selected from
substituent group A.sup.J), an aminocarbonyl group (wherein the
aminocarbonyl group is optionally substituted by one or two groups,
which may be the same or different C1-6 alkyl groups each
optionally substituted by one to three groups, which may be the
same or different, selected from substituent group A.sup.J), a
C6-10 arylaminocarbonyl group (wherein the arylaminocarbonyl group
is optionally substituted by one or two groups, which may be the
same or different, selected from substituent group A.sup.H and a
C1-6 halogenoalkyl group), a 4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur (wherein the heterocyclylcarbonyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.J), or a 3- to
10-membered heterocyclylaminocarbonyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclylaminocarbonyl
group is optionally substituted by one or two groups, which may be
the same or different, selected from substituent group A.sup.H and
a C1-6 halogenoalkyl group), or
the C1-6 alkyl groups of R.sup.2 and R.sup.3 are optionally bonded
to each other to form a 3- to 6-membered saturated carbocyclic ring
or to form a 4- to 6-membered saturated heterocyclic ring via one
nitrogen or oxygen atom (wherein one nitrogen atom in the 4- to
6-membered saturated heterocyclic ring is optionally replaced with
a hydrogen atom, a C1-6 alkyl group, a C1-6 alkylcarbonyl group, a
C1-6 alkoxycarbonyl group),
R.sup.4 and R.sup.5 are the same or different and each
represent
a hydrogen atom,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.C),
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.C), or
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.C),
R.sup.6 represents
a hydrogen atom,
a C1-6 alkyl group (R.sup.6 is a carbon substituent of the
pyridinyl ring, not a nitrogen substituent) or
a hydroxy group,
each substituent R.sup.7a.about.R.sup.7e may be the same or
different and may be each represent
a hydrogen atom,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three groups, which may be the same or
different, selected from substituent group A.sup.B),
a C6-10 aryl group (wherein the aryl group is optionally
substituted by one or two groups, which may be the same or
different, selected from substituent group A.sup.B),
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is
optionally substituted by one or two groups, which may be the same
or different, selected from substituent group A.sup.B), or a
hydroxy group, and
the substituent groups represent
A.sup.B: a hydroxy group,
a C1-6 alkoxy group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
a carboxyl group,
a C1-6 alkoxycarbonyl group,
an aminocarbonyl group (wherein the aminocarbonyl group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups),
an amino group (wherein the amino group is optionally substituted
by one or two groups, which may be the same or different C1-6 alkyl
groups),
a halogeno group, and
a cyano group;
A.sup.C: a hydroxy group,
a C1-6 alkoxy group,
an amino group (wherein the amino group is optionally substituted
by one or two groups, which may be the same or different C1-6 alkyl
groups),
a halogeno group, and
a cyano group;
A.sup.D: a C1-6 alkoxy group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
a carboxyl group,
a C1-6 alkoxycarbonyl group,
an aminocarbonyl group (wherein the aminocarbonyl group is
optionally substituted by one or two groups, which may be the same
or different C1-6 alkyl groups),
a halogeno group, and
a cyano group;
A.sup.E: a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur, and
a halogeno group;
A.sup.F: a hydroxy group,
a C1-6 alkyl group (wherein the alkyl group is optionally
substituted by one to three halogeno groups),
a C1-6 alkoxy group (wherein the alkoxy group is optionally
substituted by one to three halogeno groups),
a halogeno group,
an amino group, and
a cyano group;
A.sup.G: a hydroxy group,
a C1-6 alkoxy group,
an amino group,
a halogeno group, and
a cyano group;
A.sup.H: a hydroxy group,
a C1-6 alkoxy group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
an amino group (wherein the amino group is optionally substituted
by one or two groups, which may be the same or different C1-6 alkyl
groups),
a halogeno group, and
a cyano group;
A.sup.J: a C1-6 alkoxy group,
a C3-8 cycloalkyl group,
a C6-10 aryl group,
a 3- to 10-membered heterocyclyl group containing one to four
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur,
a halogeno group, and
a cyano group,
or a pharmacologically acceptable salt thereof.
In the present invention, the "C1-6 alkyl group" refers to a linear
or branched alkyl group having 1 to 6 carbon atoms. Examples
thereof can include methyl, ethyl, n-propyl, n-butyl, isobutyl,
s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl,
1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,
2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl groups. For
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7a.about.R.sup.7e, A.sup.B, A.sup.C, A.sup.D, A.sup.F, or
A.sup.G, the C1-6 alkyl group is preferably an alkyl group having 1
to 3 carbon atoms, most preferably an ethyl or methyl group.
In the present invention, the "C1-6 alkylcarbonyl group" refers to
the aforementioned "C1-6 alkyl group" bonded to a carbonyl group.
Examples thereof can include methylcarbonyl, ethylcarbonyl,
n-propylcarbonyl, n-butylcarbonyl, isobutylcarbonyl,
s-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl,
isopentylcarbonyl, 2-methylbutylcarbonyl, neopentylcarbonyl,
1-ethylpropylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl,
4-methylpentylcarbonyl, 3-methylpentylcarbonyl,
2-methylpentylcarbonyl, 1-methylpentylcarbonyl,
3,3-dimethylbutylcarbonyl, 2,2-dimethylbutylcarbonyl,
1,1-dimethylbutylcarbonyl, 1,2-dimethylbutylcarbonyl,
1,3-dimethylbutylcarbonyl, 2,3-dimethylbutylcarbonyl, and
2-ethylbutylcarbonyl groups. For R.sup.2 or R.sup.3, the C1-6
alkylcarbonyl group is preferably an alkylcarbonyl group having 1
to 3 carbon atoms, most preferably a methylcarbonyl group.
In the present invention, the "C3-8 cycloalkyl group" refers to a
3- to 8-membered saturated cyclic hydrocarbon group. Examples
thereof can include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl groups. For R.sup.2,
R.sup.3, A.sup.B, A.sup.D, A.sup.H, or A.sup.J, the C3-8 cycloalkyl
group is preferably a 3- to 6-membered saturated cyclic hydrocarbon
group, more preferably a cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl group.
In the present invention, the "C1-6 halogenoalkyl group" refers to
the aforementioned "C1-6 alkyl group" substituted by one to six
halogen atoms. Examples thereof can include linear or branched
halogenoalkyl groups each having 1 to 6 carbon atoms, such as
fluoromethyl, difluoromethyl, trifluoromethyl,
2,2,2-trifluoroethyl, 1,1,1,3,3,3-hexafluoro-2-propyl,
chloromethyl, 2-chloroethyl, 3-chloro-n-propyl, 4-chloro-n-butyl,
5-chloro-n-pentyl, and 6-chloro-n-hexyl groups. For R.sup.2 or
R.sup.3, the C6-10 halogenoalkyl group is preferably
trifluoromethyl group.
In the present invention, the "C6-10 aryl group" refers to an
aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples
thereof can include phenyl, indenyl, and naphthyl groups. For
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.7a.about.R.sup.7e, A.sup.B, A.sup.D, A.sup.E, A.sup.H, or
A.sup.J, the C6-10 aryl group is preferably a phenyl group.
In the present invention, the "C1-6 alkoxy group" refers to the
aforementioned "C1-6 alkyl group" bonded to an oxygen atom.
Examples thereof can include linear or branched alkoxy groups each
having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy,
isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy,
4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy,
3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy,
1,2-dimethylbutoxy, 1,3-dimethylbutoxy, and 2,3-dimethylbutoxy. For
R.sup.1, R.sup.2, R.sup.3, A.sup.B, A.sup.C, A.sup.D, A.sup.F,
A.sup.G, A.sup.H, or A.sup.J, the C1-6 alkoxy group is preferably a
methoxy or ethoxy group.
In the present invention, the "C1-6 alkoxycarbonyl group" refers to
the aforementioned "C1-6 alkoxy group" bonded to a carbonyl group.
Examples thereof can include linear or branched alkoxycarbonyl
groups each having 1 to 6 carbon atoms, such as methoxycarbonyl,
ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,
n-butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl,
tert-butoxycarbonyl, n-pentoxycarbonyl, isopentoxycarbonyl,
2-methylbutoxycarbonyl, neopentoxycarbonyl, n-hexyloxycarbonyl,
4-methylpentoxycarbonyl, 3-methylpentoxycarbonyl,
2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl,
2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl,
1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, and
2,3-dimethylbutoxycarbonyl. For R.sup.1, R.sup.2, R.sup.3, A.sup.B,
or A.sup.D, the C1-6 alkoxycarbonyl group is preferably a
methoxycarbonyl or ethoxycarbonyl group.
In the present invention, the "4- to 7-membered saturated
heterocyclyl group containing one or two heteroatoms, which may be
the same or different, selected from nitrogen, oxygen, and sulfur"
refers to a 4- to 7-membered saturated heterocyclic group
containing one or two atoms of nitrogen, oxygen, and sulfur.
Examples thereof can include oxetanyl, morpholinyl,
thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl,
tetrahydrofuranyl, tetrahydropyranyl, and
5-oxo-4,5-dihydro-1,2,4-oxadiazolyl groups.
In the present invention, the "4- to 7-membered saturated
heterocyclylcarbonyl group containing one or two heteroatoms, which
may be the same or different, selected from nitrogen, oxygen, and
sulfur" refers to the aforementioned "4- to 7-membered saturated
heterocyclyl group containing one or two heteroatoms, which may be
the same or different, selected from nitrogen, oxygen, and sulfur"
bonded to a carbonyl group. Examples thereof can include
morpholinylcarbonyl, thiomorpholinylcarbonyl, pyrrolidinylcarbonyl,
pyrrolinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl,
tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, and
5-oxo-4,5-dihydro-1,2,4-oxadiazolylcarbonyl groups.
In the present invention, the "4- to 7-membered saturated
heterocyclylcarbonyloxy group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur" refers to the aforementioned "4- to 7-membered
saturated heterocyclylcarbonyl group containing one or two
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur" bonded to an oxygen atom. Examples
thereof can include morpholinylcarbonyloxy,
thiomorpholinylcarbonyloxy, pyrrolidinylcarbonyloxy,
pyrrolinylcarbonyloxy, piperidinylcarbonyloxy,
piperazinylcarbonyloxy, tetrahydrofuranylcarbonyloxy,
tetrahydropyranylcarbonyloxy, and
5-oxo-4,5-dihydro-1,2,4-oxadiazolylcarbonyloxy groups.
In the present invention, the "3- to 10-membered heterocyclyl group
containing one to four heteroatoms, which may be the same or
different, selected from nitrogen, oxygen, and sulfur" refers to a
3- to 10-membered heterocyclic group containing one to four atoms
of nitrogen, oxygen, and sulfur. Examples thereof can include the
groups listed as the examples of the aforementioned "4- to
7-membered heterocyclyl group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur", and aromatic heterocyclic groups such as furyl,
thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl,
oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl,
1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl,
pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The "3- to
10-membered heterocyclic group" may be condensed with an additional
cyclic group. Examples thereof can include benzofuranyl, chromenyl,
indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl,
isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
quinazolinyl, isoindolinyl, 2,3-dihydro-1-benzofuranyl,
3,4-dihydro-1H-isochromenyl, 1,2,3,4-tetrahydroquinolinyl, and
1,2,3,4-tetrahydroisoquinolinyl groups.
In the present invention, the "3- to 10-membered
heterocyclylcarbonyl group containing one to four heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur" refers to the aforementioned "3- to 10-membered
heterocyclyl group containing one to four heteroatoms, which may be
the same or different, selected from nitrogen, oxygen, and sulfur"
bonded to a carbonyl group. Examples thereof can include the groups
listed as the examples of the aforementioned "4- to 7-membered
saturated heterocyclylcarbonyl group containing one or two
heteroatoms, which may be the same or different, selected from
nitrogen, oxygen, and sulfur", bonded to a carbonyl group such as
furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, azepinylcarbonyl,
pyrazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl,
oxadiazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl,
isothiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl,
tetrazolylcarbonyl, thiadiazolylcarbonyl, pyranylcarbonyl,
pyridylcarbonyl, pyridazinylcarbonyl, pyrimidinylcarbonyl, and
pyrazinylcarbonyl groups.
In the present invention, the "3- to 10-membered
heterocyclylaminocarbonyl group containing one or two heteroatoms,
which may be the same or different, selected from nitrogen, oxygen,
and sulfur" refers to the aforementioned "3- to 10-membered
heterocyclyl group containing one to four heteroatoms, which may be
the same or different, selected from nitrogen, oxygen, and sulfur"
bonded to a carbonyl group via an amino group. Examples thereof can
include such as furylaminocarbonyl, thienylaminocarbonyl,
pyrrolylaminocarbonyl, azepinylaminocarbonyl,
pyrazolylaminocarbonyl, imidazolylaminocarbonyl,
oxazolylaminocarbonyl, oxadiazolylaminocarbonyl,
isoxazolylaminocarbonyl, thiazolylaminocarbonyl,
isothiazolylaminocarbonyl, 1,2,3-oxadiazolylaminocarbonyl,
triazolylaminocarbonyl, tetrazolylaminocarbonyl,
thiadiazolylaminocarbonyl, pyranylaminocarbonyl,
pyridylaminocarbonyl, pyridazinylaminocarbonyl,
pyrimidinylaminocarbonyl, and pyrazinylaminocarbonyl groups.
In the present invention, the "halogeno group" refers to a fluoro,
chloro, bromo, or iodo group. For R.sup.1, R.sup.2, R.sup.3,
A.sup.B, A.sup.C, A.sup.D, A.sup.E, A.sup.F, A.sup.G, A.sup.H, or
A.sup.J, the halogeno group is preferably a fluoro, chloro, or
bromo group.
Preferably, each R.sup.1 of the present invention, which may be the
same or different, represents a C1-6 alkoxy group or a halogeno
group.
Preferably, X of the present invention is --CH.dbd. or
--N.dbd..
Preferably, A of the invention is one of the following general
formula (IIIa)(IIId)
##STR00010##
Preferably, R.sup.2 and R.sup.3 of the present invention are the
same or different and each represent a hydrogen atom or a C1-6
alkyl group, or the C1-6 alkyl groups of R.sup.2 and R.sup.3 are
bonded to each other to form a 3- to 6-membered saturated
carbocyclic ring.
Preferably, each of R.sup.4 and R.sup.5 of the present invention is
a hydrogen atom.
Preferably, R.sup.6 of the present invention is a hydrogen
atom.
Preferably, R.sup.7 of the present invention is a hydrogen atom or
a C1-6 alkyl group.
The compound represented by the general formula (I) of the present
invention can form a salt with a base. Such a salt with a base is
included in the scope of the present invention. Examples of the
salt with a base can include: alkali metal salts such as lithium
salt, sodium salt, potassium salt, and cesium salt; alkaline earth
metal salts such as magnesium salt, calcium salt, and barium salt;
inorganic nitrogen compound salts such as ammonium salt and
hydrazine salt; primary amine salts such as methylamine salt,
ethylamine salt, n-propylamine salt, isopropylamine salt,
n-butylamine salt, 2-butylamine salt, isobutylamine salt, and
tert-butylamine salt; secondary amine salts such as dimethylamine
salt, diethylamine salt, diisopropylamine salt, pyrrolidine salt,
piperidine salt, and morpholine salt; tertiary amine salts such as
triethylamine salt and N-methylmorpholine salt; and aromatic amine
salts such as pyridine salt, 4-(N,N-dimethylamino)pyridine salt,
imidazole salt, and 1-methylimidazole salt. The salt is preferably
an alkali metal salt, most preferably sodium salt or potassium
salt. The compound represented by the general formula (I) of the
present invention can form any ratio of a salt with a base. The
respective salts with bases or mixtures thereof are included in the
scope of the present invention.
The compound represented by the general formula (I) of the present
invention can form an acid-addition salt, depending on its
substituent. Such an acid-addition salt is included in the scope of
the present invention. The compound represented by the general
formula (I) of the present invention can form any ratio of an
acid-addition salt, depending on its substituent. The respective
acid addition salts (e.g., monoacid salt and hemi-acid salt) or
mixtures thereof are included in the salt of the present
invention.
The compound represented by the general formula (I) of the present
invention or the pharmacologically acceptable salt thereof can form
an anhydrate, a hydrate, or a solvate. The respective forms or
mixtures thereof are included in the scope of the present
invention.
When the compound represented by the general formula (I) of the
present invention or the pharmacologically acceptable salt thereof
has at least one asymmetric center, carbon-carbon double bond,
axial chirality, tautomerism, or the like, optical isomers
(including enantiomers and diastereomers), geometric isomers,
rotational isomers, and tautomers may exist. These isomers and
mixtures thereof are represented by a single formula such as the
formula (I). The present invention encompasses these isomers and
mixtures (including racemates) thereof at any ratio.
The compound represented by the general formula (I) of the present
invention or the pharmacologically acceptable salt thereof can form
an isotopic compound by the replacement of one or more atoms
constituting the compound or the salt with isotopes at nonnatural
ratios. The isotopes can be radioactive or nonradioactive. Examples
thereof include deuterium (.sup.2H; D), tritium (.sup.3H; T),
carbon-13 (.sup.13C), carbon-14 (.sup.14C), and iodine-125
(.sup.125I). The radioactive or nonradioactive isotopic compound
may be used as a pharmaceutical for the treatment or prophylaxis of
a disease, a reagent for research (e.g., a reagent for assay), a
diagnostic agent (e.g., a diagnostic imaging agent), or the like.
The present invention encompasses these radioactive or
nonradioactive isotopic compounds.
The compound represented by the general formula (I) of the present
invention can be produced by, for example, the following
method:
Method A
When A is represented by the general formula (IIa), the compound
represented by the general formula (I) of the present invention can
be produced by the method A.
##STR00011## Method B
When A is represented by the general formula (IIb), the compound
represented by the general formula (I) of the present invention can
be produced by the method B.
##STR00012## Method C
When A is represented by the general formula (IIc), the compound
represented by the general formula (I) of the present invention can
be produced by the method C.
##STR00013## Method D
When A is represented by the general formula (IId), the compound
represented by the general formula (I) of the present invention can
be produced by the method D.
##STR00014## Method E
When A is represented by the general formula (IIe), the compound
represented by the general formula (I) of the present invention can
be produced by the method E.
##STR00015## Method F
When A is represented by the general formula (IIf), the compound
represented by the general formula (I) of the present invention can
be produced by the method F.
##STR00016##
In the structural formulas of the compounds in the method A, method
B, method C, method D, method E and method F, and the description
below, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.7a-e, R.sup.8f, m, n and X are as defined in the formula
(I);
L.sup.1 represents a nitro group, a halogeno group, or an amino
group (wherein the amino group is optionally substituted by a C1-6
alkoxycarbonyl group), and is preferably a nitro group or a bromo
group;
L.sup.2 represents a halogeno group and is preferably a fluoro
group or a chloro group;
L.sup.3 represents a hydrogen atom or a C1-6 alkyl group (wherein
the alkyl group is optionally substituted by an ethenyl group, a
phenyl group, a 4-methoxyphenyl group or a 2,4-dimethoxyphenyl
group), and is preferably a 2,4-dimethoxybenzyl group;
L.sup.4 represents C1-6 alkoxy group, a halogeno group, or an amino
group (wherein the amino group is optionally substituted by one or
two groups, which may be the same or different C1-6 alkyl groups,
or a C1-6 alkyl group and a C1-6 alkoxy group), and is preferably a
dimethylamino group or a N,O-dimethylhydroxyamino group; L.sup.5
represents a hydrogen atom, a C1-6 alkyl group (wherein the alkyl
group is optionally substituted by an ethenyl group, a phenyl
group, or a 4-methoxyphenyl group) or a silyl group (wherein the
silyl group is substituted by three groups, which may be the same
or different C1-6 alkyl groups or phenyl groups), and is preferably
tert-butyldimethylsilyl group or tert-butyldiphenylsilyl group;
L.sup.6 represents a halogeno group or a sulfonate group (wherein
the sulfonate group is substituted by a methyl group, a
trifluoromethyl group, or a 4-methylphenyl groups), and is and is
preferably a bromo group; and L.sup.7 represents C1-6 alkoxy group,
or an amino group (wherein the amino group is optionally
substituted by one or two groups, which may be the same or
different C1-6 alkyl groups, or a C1-6 alkyl group and a C1-6
alkoxy group), and is preferably a dimethylamino group or a
N,O-dimethylhydroxyamino group.
When a compound serving as a reactive substrate in the reaction of
each step in the method A, method B, method C, method D and method
E has a group inhibiting the reaction of interest, such as an amino
group, a hydroxy group, or a carbonyl group, an appropriate
protective group may be introduced to the functional group and the
introduced protective group may be removed, if necessary. Such a
protective group is not particularly limited as long as the
protective group is one usually used. The protective group can be a
protective group described in, for example, T. W. Greene, P. G. M.
Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014,
John Wiley & Sons, Inc. The reactions for the introduction and
removal of these protective groups can be carried out according to
routine methods such as methods described in the literature.
The solvent for use in the reaction of each step in the method A,
method B, method C, method D and method E is not particularly
limited as long as the solvent partially dissolves starting
materials without inhibiting the reaction. The solvent is selected
from, for example, the following solvent group: aliphatic
hydrocarbons such as hexane, pentane, heptane, petroleum ether, and
cyclohexane; aromatic hydrocarbons such as toluene, benzene, and
xylene; halogenated hydrocarbons such as methylene chloride,
chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
and dichlorobenzene; ethers such as diethyl ether, diisopropyl
ether, cyclopentylmethyl ether, t-butyl methyl ether,
tetrahydrofuran, 1,4-dioxane, dimethoxyethane, and diethylene
glycol dimethyl ether; ketones such as acetone, methyl ethyl
ketone, methyl isobutyl ketone, and cyclohexanone; esters such as
methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and
diethyl carbonate; nitriles such as acetonitrile, propionitrile,
butyronitrile, and isobutyronitrile; organic acids such as formic
acid, acetic acid, propionic acid, trifluoroacetic acid, and
pentafluoropropionic acid; alcohols such as methanol, ethanol,
1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol,
and 2-methyl-2-propanol; amides such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,
N,N'-dimethylpropyleneurea, and hexamethylphosphortriamide;
sulfoxides such as dimethyl sulfoxide and sulfolane; water; and
mixtures thereof.
The acid for use in the reaction of each step in the method A,
method B, method C, method D and method E mentioned below is not
particularly limited as long as the acid does not inhibit the
reaction. The acid is selected from the following acid group:
inorganic acids such as hydrochloric acid, hydrobromic acid,
hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid;
organic acids such as formic acid, acetic acid, propionic acid,
trifluoroacetic acid, and pentafluoropropionic acid; and organic
sulfonic acids such as methanesulfonic acid,
trifluoromethanesulfonic acid, p-toluenesulfonic acid, and
camphorsulfonic acid.
The base for use in the reaction of each step in the method A,
method B, method C, method D and method E mentioned below is not
particularly limited as long as the base does not inhibit the
reaction. The base is selected from the following base group:
alkali metal carbonates such as lithium carbonate, sodium
carbonate, potassium carbonate, and cesium carbonate; alkali metal
bicarbonates such as lithium bicarbonate, sodium bicarbonate, and
potassium bicarbonate; alkali metal hydroxides such as lithium
hydroxide, sodium hydroxide, and potassium hydroxide; alkaline
earth metal hydroxides such as calcium hydroxide and barium
hydroxide; alkali metal phosphates such as sodium phosphate and
potassium phosphate; alkali metal hydrides such as lithium hydride,
sodium hydride, and potassium hydride; alkali metal amides such as
lithium amide, sodium amide, and potassium amide; metal alkoxides
such as lithium methoxide, sodium methoxide, sodium ethoxide,
sodium tert-butoxide, and potassium tert-butoxide; lithium amides
such as lithium diisopropylamide (LDA), lithium
cyclohexylisopropylamide, and lithium tetramethylpiperazide; alkali
metal silylamides such as lithium bistrimethylsilylamide, sodium
bistrimethylsilylamide, and potassium bistrimethylsilylamide;
alkyllithiums such as methyllithium, n-butyllithium,
sec-butyllithium, and tert-butyllithium; alkyl magnesium halides
such as methyl magnesium chloride, methyl magnesium bromide, methyl
magnesium iodide, ethyl magnesium chloride, ethyl magnesium
bromide, isopropyl magnesium chloride, isopropyl magnesium bromide,
and isobutyl magnesium chloride; and organic amines such as
triethylamine, tributylamine, diisopropylethylamine, diethylamine,
diisopropylamine, N-methylpiperidine, N-methylmorpholine,
N-ethylmorpholine, pyridine, picoline, 2,6-lutidine,
4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline,
N,N-diethylaniline, 1,5-diazabicyclo[4,3,0]non-5-ene,
1,4-diazabicyclo[2,2,2]octane (DABCO), and
1,8-diazabicyclo[5,4,0]-7-undecene (DBU).
In the reaction of each step in the method A, method B, method C,
method D and method E mentioned below, the reaction temperature
differs depending on solvents, starting materials, reagents, etc.,
and the reaction time differs depending on solvents, starting
materials, reagents, etc.
After the completion of the reaction of each step in the method A,
method B, method C, method D and method E mentioned below, the
compound of interest of each step is isolated from the reaction
mixture according to a routine method. The compound of interest is
obtained, for example, by: (i) if necessary, filtering off
insoluble matter such as a catalyst; (ii) adding water and a
water-immiscible solvent (e.g., methylene chloride, chloroform,
diethyl ether, ethyl acetate, or toluene) to the reaction mixture
to extract the compound of interest; (iii) washing the organic
layer with water, followed by drying using a desiccant such as
anhydrous sodium sulfate or anhydrous magnesium sulfate; and (iv)
distilling off the solvent. The obtained compound of interest can
be further purified, if necessary, by a routine method, for
example, recrystallization, reprecipitation, or silica gel column
chromatography. Alternatively, the compound of interest of each
step may be used directly in the next reaction without being
purified.
In the reaction of each step in the method A, method B, method C,
method D and method E mentioned below, optical isomers can be
resolved by resolution using a chiral column.
Hereinafter, the reaction of each step in the method A, method B,
method C, method D and method E will be described.
(Step A-1)
Step A-1 is the step of condensing compound (1) with compound (2)
to produce compound (3). The compound (1) and (2) are known in the
art or is easily obtained from a compound known in the art.
The method for condensing a carboxylic acid with an amine differs
depending on the type of the carboxylic acid and can be generally
carried out by a method well known in the techniques of organic
synthetic chemistry, for example, a method described in
Comprehensive Organic Transformations (Second Edition, 1999, John
Wiley & Sons, Inc., pp. 1929-1930, 1941-1949, and 1953-1954). A
preferred method involves converting the carboxylic acid to a
corresponding acid halide, which is then condensed with a
corresponding amine. Thus, step A-1 comprises:
(step A-1-1): the step of reacting compound (1) with a halogenating
agent; and
(step A-1-2): the step of reacting the compound obtained in the
step A-1-1 with compound (2) in the presence of a base.
(Step A-1-1)
Examples of the halogenating agent used can include: thionyl
chloride, phosphorus trichloride, phosphorus oxychloride,
phosphorus pentachloride, phosphorus tribromide, phosphorus
pentabromide, oxalyl chloride, carbon
tetrachloride-triphenylphosphine,
hexachloroethane-triphenylphosphine,
N-chlorosuccinimide-triphenylphosphine, carbon
tetrabromide-triphenylphosphine, and
N-bromosuccinimide-triphenylphosphine; and combinations of these
halogenating agents with additives such as N,N-dimethylformamide.
The halogenating agent is preferably a combination of thionyl
chloride with an additive or a combination of oxalyl chloride with
an additive, more preferably a combination of oxalyl chloride with
N,N-dimethylformamide.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, and
esters. The solvent is preferably a halogenated hydrocarbon or an
ether, more preferably methylene chloride or tetrahydrofuran.
The reaction temperature is preferably 0.degree. C. to 100.degree.
C., more preferably room temperature.
The reaction time is preferably 15 minutes to 6 hours.
(Step A-1-2)
Examples of the base used can include alkali metal carbonates,
alkali metal bicarbonates, alkali metal hydrides, lithium amides,
alkali metal silylamides, alkyllithiums, and organic amines. The
base is preferably an organic amine, more preferably triethylamine
or diisopropylethylamine.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters,
and amides. The solvent is preferably an ether or an amide, more
preferably tetrahydrofuran or N,N-dimethylformamide.
The reaction temperature is preferably -78.degree. C. to
100.degree. C., more preferably -20.degree. C. to room
temperature.
The reaction time is preferably 15 minutes to 24 hours.
(Step A-2)
Step A-2 is the step of intramolecularly cyclizing the compound (3)
obtained in the step A-1-2 in the presence of a base to produce
compound (4). The compound (4) of interest of this step can also be
converted, if necessary, to another compound (4) of interest
through deprotection reaction. The method for converting the
obtained compound (4) of interest to another compound (4) of
interest by the removal of the protective group differs depending
on the type of the protective group and can be generally carried
out according to a routine method such as a method well known in
the techniques of organic synthetic chemistry, for example, a
method described in T. W. Greene, P. G. M. Wuts, Protective Groups
in Organic Synthesis Fifth Edition, 2014, John Wiley & Sons,
Inc.
When L.sup.3 is a 2,4-dimethoxybenzyl group, the method is
preferably a method using an acid in the presence of a cation
scavenger. Thus, step A-2 comprises:
(step A-2-1): the step of intramolecularly cyclizing the compound
(3) obtained in the step A-1-2 in the presence of a base to produce
compound (4); and
(step A-2-1): the step of deprotection reaction of the compound (4)
of interest obtained in the step A-2-1 to produce another compound
(4).
(Step A-2-1)
Examples of the base used can include alkali metal carbonates,
alkali metal bicarbonates, alkali metal hydrides, alkali metal
hydroxides, alkaline earth metal hydroxides, alkali metal
alkoxides, lithium amides, alkali metal silylamides, and organic
amines. The base is preferably an alkali metal hydride, an alkali
metal carbonate, an alkali metal silylamide, or an organic amine,
more preferably sodium bistrimethylsilylamide, sodium hydride,
potassium carbonate, or cesium carbonate.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, and amides. The solvent is preferably an
ether, a nitrile, or an amide, more preferably tetrahydrofuran,
acetonitrile, or N,N-dimethylformamide.
The reaction temperature is preferably -78.degree. C. to
100.degree. C.
The reaction time is preferably 15 minutes to 24 hours.
(Step A-2-2)
Examples of the acid used can include inorganic acids, organic
acids, organic sulfonic acids and mixtures thereof. The acid is
preferably a mixture of an organic acid and an organic sulfonic
acid, more preferably a mixture of trifluoroacetic acid and
trifluoromethanesulfonic acid.
Examples of the cation scavenger used can include anisole,
thioanisole, isoamylene, triethylsilane, triisopropylsilane, and
triphenylphosphine. The cation scavenger is preferably anisole.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, and halogenated hydrocarbons. The solvent is
preferably a halogenated hydrocarbon, more preferably
chloroform.
The reaction temperature is preferably -10.degree. C. to 60.degree.
C.
The reaction time is preferably 30 minutes to 6 hours.
(Step A-3)
Step A-3 is the step of reacting the compound (4) obtained in step
A-2-2 with compound (5) to produce compound (6). The compound (5)
is known in the art or is easily obtained from a compound known in
the art.
The method for triazole ring formation from an amide differs
depending on the type of the amide and is not particularly limited
as long as the reaction does not influence the other parts of the
compound. This reaction can be carried out by, for example, a
method involving converting the amide to a chloroimidate, which is
then reacted with a corresponding hydrazide, described in L. Johan,
J. Martin, Synthetic Communications, 36, 2217 (2006), and a method
involving converting the amide to a thioimidate, which is then
reacted with a corresponding hydrazide, described in K. D. Robarge,
M. S. Dina, T. C. Somers, A. Lee, T. E. Rawson, A. G. Olivero, M.
H. Tischler, R. R. Webb II, K. J. Weese, I. Aliagas, B. K.
Blackburn, Bioorganic and Medicinal Chemistry, 6, 2345 (1998).
The method is preferably a method involving converting the amide to
a thioimidate, which is then reacted with a corresponding
hydrazide. Thus, step A-3 comprises:
(Step A-3-1): the step of reacting the compound (4) obtained in
step A-2-2 with a sulfurizing agent to produce a thioamide;
(Step A-3-2): the step of reacting the thioamide obtained in step
A-3-1 with an alkylating agent in the presence of base to produce a
thioimidate; and
(Step A-3-3): the step of reacting the thioimideate obtained in
step A-3-2 with compound (5) in the presence or absence of an
additive to produce compound (6).
(Step A-3-1)
The sulfurizing agent is preferably
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide
(Lawesson's reagent).
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, and
mixtures thereof. The solvent is preferably an ether, more
preferably tetrahydrofuran.
The reaction temperature is preferably 0.degree. C. to 65.degree.
C.
The reaction time is preferably 30 minutes to 24 hours.
(Step A-3-2)
Examples of the alkylating agent used can include methyl halides,
ethyl halides, allyl halides, benzyl halids, methyl sulfonates,
ethyl sulfonates trimethyloxisonium salts and triethyloxisonium
salts. The alkylating agent is preferably methyl halides, and more
preferably methyl iodide.
Examples of the base used can include alkali metal carbonates,
alkali metal hydrides, lithium amides, and alkali metal
silylamides. The base is preferably an alkali metal hydride, more
preferably sodium hydride.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters,
nitriles, ketones, and amides. The solvent is preferably an ether
or an amide, more preferably tetrahydrofuran or
N,N-dimethylformamide.
The reaction temperature is preferably -20.degree. C. to 60.degree.
C.
The reaction time is preferably 15 minutes to 6 hours.
(Step A-3-3)
Examples of the additive used can include inorganic acids, organic
acids, organic sulfonic acids.
Alternatively, the additive may not be used. Preferably, the
additive is not used.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers
and mixtures thereof. The solvent is preferably an alcohol, more
preferably ethanol.
The reaction temperature is preferably room temperature to
100.degree. C.
The reaction time is preferably 1 hour to 48 hours.
(Step A-4)
Step A-4 is the step of reacting the compound (6) obtained in the
step A-3-3 with compound (7) in the presence of a base to produce
compound (I). The compound (7) is known in the art or is easily
obtained from a compound known in the art.
Hereinafter, this step is referred to as step A-4-1 when L.sup.1 is
a nitro group, as step A-4-2 when L.sup.1 is an amino group, and as
step A-3-3 when L.sup.1 is a halogeno group.
(Step A-4-1)
When L.sup.1 is a nitro group, step A-4-1 comprises:
(step A-4-1a): the step of selectively reducing the nitro group of
the compound obtained in the step A-3-3 into an amino group;
and
(step A-4-1b): the step of reacting the compound obtained in the
step A-4-1a with compound (7) in the presence of a base to produce
compound (I).
(Step A-4-1a)
The method for selectively reducing the nitro group is not
particularly limited as long as the method does not influence the
other parts of the compound. This method can be generally carried
out by a method well known in the techniques of organic synthetic
chemistry, for example, a method described in Comprehensive Organic
Transformations (Second Edition, 1999, John Wiley & Sons, Inc.,
pp. 821-828). The method is preferably a catalytic reduction method
or a method using a combination of a reducing agent and an
additive.
Examples of the metal catalyst for use in the catalytic reduction
method can include: palladium catalysts such as palladium on
carbon, palladium black, palladium hydroxide on carbon, and
palladium on barium sulfate; platinum catalysts such as platinum
oxide and platinum black, platinium on carbon; rhodium catalysts
such as rhodium on aluminum oxide and
chlorotris(triphenylphosphine)rhodium (I); and nickel catalysts
such as Raney nickel. The metal catalyst is preferably a palladium
catalyst, more preferably 10% palladium on carbon.
The hydrogen pressure in the catalytic reduction method is
preferably 1 to 10 atm, more preferably 1 atm.
The solvent for use in the catalytic reduction method is not
particularly limited as long as the solvent is inert to this
reaction. Examples thereof can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, amides, and mixtures thereof. The
solvent is preferably an alcohol, an ether, an amide, or a mixture
thereof, more preferably methanol or a mixture of tetrahydrofuran
and ethanol.
The reaction temperature in the catalytic reduction method is
preferably room temperature to 60.degree. C.
The reaction time in the catalytic reduction method is preferably 1
hour to 24 hours.
The combination of the reagents for use in the reaction using the
combination of the reducing agent and the additive is preferably a
combination of sodium borohydride and nickel(II) chloride
hexahydrate, a combination of zinc powder and acetic acid, a
combination of iron powder and acetic acid, or a combination of
tin(II) chloride and hydrochloric acid, more preferably a
combination of sodium borohydride and nickel(II) chloride
hexahydrate.
The solvent for use in the reaction using the combination of the
reducing agent and the additive is preferably a mixture of an
alcohol and an ether, more preferably a mixture of tetrahydrofuran
and methanol.
The reaction temperature in the reaction using the combination of
the reducing agent and the additive is preferably 0.degree. C. to
room temperature.
The reaction time in the reaction using the combination of the
reducing agent and the additive is preferably 5 minutes to 2
hours.
(Step A-4-1b)
Examples of the base used can include alkali metal carbonates,
alkali metal bicarbonates, alkali metal hydrides, alkali metal
hydroxides, alkali metal alkoxides, lithium amides, alkali metal
silylamides, and organic amines. The base is preferably an organic
amine, more preferably pyridine.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters,
nitriles, ketones, and amides. Alternatively, the solvent may not
be used. Preferably, the solvent is not used.
The reaction temperature is preferably 0.degree. C. to 100.degree.
C., more preferably room temperature to 80.degree. C.
The reaction time is preferably 5 minutes to 24 hours, more
preferably 15 minutes to 3 hours.
The reaction for converting the obtained compound (I) of interest
obtained in this step to another compound (I) of interest by the
removal of the protective group is not particularly limited as long
as the reaction does not influence the other parts of the compound.
This reaction can be carried out according to a routine method, for
example, a method described in T. W. Greene, P. G. M. Wuts,
Protective Groups in Organic Synthesis, Fifth Edition, 2014, John
Wiley & Sons, Inc.
(Step A-4-2)
When L.sup.1 is an amino group, the compound (I) can be produced
according to the step A-4-1b.
(Step A-4-3)
When L.sup.1 is a halogeno group, step A-4-3 comprises:
(step A-4-3a): the step of converting the bromo group of the
compound produced in the step A-3-3 to a N-Boc amide group using a
metal catalyst in the presence of a base;
(step A-4-3b): the step of deprotecting the N-Boc group of the
compound obtained in the step A-4-3a to form an amino group;
and
(step A-4-3c): the step of reacting the compound obtained in the
step A-4-3b with compound (7) in the presence of a base to produce
compound (I).
(Step A-4-3a)
The method for converting the bromo group on the aromatic ring to a
N-Boc amide group is not particularly limited as long as the method
does not influence the other parts of the compound. This method can
be carried out according to a method well known in the techniques
of organic synthetic chemistry, for example, a method described in
A. P. Dishington, P. D. Johnson, J. G. Kettle, Tetrahedron Letters,
45, 3733 (2004) or S. Bhagwanth, A. G. Waterson, G. M. Adjabeng, K.
R. Hornberger, Journal of Organic Chemistry, 74, 4634 (2009).
The metal catalyst used is preferably a combination of
tris(dibenzylideneacetone)dipalladium(0) chloroform complex and
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos.TM.) or a
combination of tris(dibenzylideneacetone)dipalladium(0) chloroform
complex and
di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine
(tBuXPhos.TM.).
The base used is preferably an alkali metal carbonate, an alkali
metal phosphate, or an alkali metal alkoxide, and more preferably
potassium carbonate, cesium carbonate, potassium phosphate, or
sodium tert-butoxide.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, amides, and mixtures thereof. The
solvent is preferably an aromatic hydrocarbon, an ether, a nitrile,
or an amide, more preferably toluene, 1,4-dioxane, acetonitrile, or
N,N-dimethylformamide.
The reaction temperature is preferably room temperature to
100.degree. C.
The reaction time is preferably 1 hour to 48 hours.
(Step A-4-3b)
The method for deprotecting the N-Boc group is not particularly
limited as long as the method does not influence the other parts of
the compound. This method can be carried out according to a routine
method, for example, a method described in T. W. Greene, P. G. M.
Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014,
John Wiley & Sons, Inc., pp. 930-946.
(Step A-4-3c)
The compound (I) can be produced according to the step A-4-1b.
When L.sup.1 is a bromo group, the compound (I) can also be
produced through the reaction of the compound (6) with the
following compound (28):
##STR00017## using a metal catalyst in the presence of a base.
The method for converting the bromo group on the aromatic ring to
an arylsulfonamide group is not particularly limited as long as the
method does not influence the other parts of the compound. This
method can be carried out according to a method well known in the
techniques of organic synthetic chemistry, for example, a method
described in X. Wang, A. Guram, M. Ronk, J. E. Milne, J. S. Tedrow
and M. M. Faul, Tetrahedron Letters, 53, 7 (2012), W. Deng, L. Liu,
C. Zhang, M. Liu, and Q.-X. Guo, Tetrahedron Letters, 46, 7295
(2005), or D. K. Luci, J. B. Jameson, A. Yasgar, G. Diaz, N. Joshi,
A. Kantz, K. Markham, S. Perry, N. Kuhn, J. Yeung, E. H. Kerns, L.
Schultz, M. Holinstat, J. Nadler, D. A. Taylor-Fishwick, A. Jadhav,
A. Simeonov, T. R. Holman and D. J. Maloney, Journal of Medicinal
Chemistry, 57, 495 (2014).
The metal catalyst used is preferably a combination of copper(I)
iodide and N-methyl-2-(methylamino)ethylamine, or a combination of
copper(I) iodide and
trans-N,N'-dimethylcyclohexane-1,2-diamine.
The base used is preferably an alkali metal carbonate, an alkali
metal phosphate, or an alkali metal alkoxide, more preferably
potassium carbonate, cesium carbonate, or potassium phosphate.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, amides, and mixtures thereof. The
solvent is preferably an aromatic hydrocarbon, an ether, a nitrile,
or an amide, more preferably xylene, 1,4-dioxane, acetonitrile, or
N,N-dimethylformamide.
The reaction temperature is preferably room temperature to
100.degree. C.
The reaction time is preferably 1 hour to 48 hours.
(Step B-1)
Step B-1 is the step of aminating compound (8) to produce compound
(9).
The method for aminating a 3-aminopyridine to produce a
3-hydrazinopyridine is not particularly limited as long as the
method does not influence the other parts of the compound. This
method can be carried out according to a method well known in the
techniques of organic synthetic chemistry, for example, a method
described in D. Thomae, M. Jeanty, J. Coste, G. Guillaumet and F.
Suzenet, European Journal of Organic Chemistry, 16, 3328 (2013), H.
Y. Lo, C. C. Man, R. W. FlecK, N. A. Neil, R. H. Ingraham, A.
Kukulka, J. R. Proudfoot, R. Betageri, T. Kirrane, U. Patel, R.
Sharma, M. A. Hoermann, A. Kabcenell, and S. D. Lombaert,
Bioorganic and Medicinal Chemistry Letters, 20, 6379 (2010), or N.
Lachance, L.-P. Bonhomme-Beaulieu and P. Joly, Synthesis, 2009,
721.
(Step B-2)
Step B-2 is the step of reacting compound (9) obtained in the step
B-1 with compound (10) in the presence or absence of an additive to
produce compound (11). The compound (10) is known in the art or is
easily obtained from a compound known in the art. The method for
reacting a hydrazine with an .alpha.,.beta.-unsaturated ketone to
produce a pyrazole is not particularly limited as long as the
method does not influence the other parts of the compound. This
method can be carried out according to a method well known in the
techniques of organic synthetic chemistry, for example, a method
described in K. Y. Chang, S. H. Kim, G. Nam, J. H. Seo, J. H. Kim
and D.-C. Ha, Bioorganic and Medicinal Chemistry Letters, 10, 1211
(2000).
Examples of the additive used can include: inorganic acids such as
hydrochloric acid; organic acids such as acetic acid,
trifluoroacetic acid; and organic sulfonic acids such as
methanesulfonic acid, p-toluenesulfonic acid; alkali metal
carbonates such as sodium carbonate, potassium carbonate, and
cesium carbonate; alkali metal bicarbonates such as sodium
bicarbonate; organic amines such as triethylamine,
diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine.
Alternatively, the additive may not be used. The additive is
preferably an alkali metal carbonate, more preferably sodium
carbonate or potassium carbonate.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
water and mixtures thereof. The solvent is preferably an alcohol or
a mixture of an alcohol and water, more preferably methanol or a
mixture of methanol and water.
The reaction temperature is preferably room temperature to
65.degree. C.
The reaction time is preferably 1 hour to 24 hours.
The compound (11) of interest of this step can also be converted,
if necessary, to another compound (11) of interest through
deprotection reaction. The method for converting the obtained
compound (11) of interest to another compound (11) of interest by
the removal of the protective group differs depending on the type
of the protective group and can be generally carried out according
to a routine method such as a method well known in the techniques
of organic synthetic chemistry, for example, a method described in
T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis
Fifth Edition, 2014, John Wiley & Sons, Inc.
(Step B-3)
Step B-3 is the step of cyclizing compound (11) obtained in the
step B-2 in the presence of a base to produce compound (12).
When L.sup.5 is a silyl group, the compound (12) can be produced by
deprotection reaction of the silyl group. The method for
deprotection reaction is preferably a method using a base.
Examples of the base used can include an alkali metal hydroxides,
alkaline earth metal hydroxides, an alkali metal fluorides, or
tetra(C1-6 alkyl)ammonium fluorides. The base is preferably a
tetra(C1-6 alkyl)ammonium fluoride, and more preferably
tetra-n-butylammonium fluoride.
The solvent used is preferably an ether, and more preferably
tetrahydrofuran.
The reaction temperature is preferably room temperature to
65.degree. C.
The reaction time is preferably 1 hour to 48 hours.
When L.sup.5 is a hydrogen atom, the compound (12) can be produced
according to the Step A-2-1.
(Step B-4)
Step B-4 is the step of reacting the compound (12) obtained in the
step B-3 with compound (7) in the presence of a base to produce
compound (I).
When L.sup.1 is a nitro group, the compound (I) can be produced
according to the step A-4-1.
When L.sup.1 is an amino group, the compound (I) can be produced
according to the step A-4-1b.
When L.sup.1 is a halogeno group, the compound (I) can be produced
according to the step A-4-3.
(Step C-1)
Step C-1 is the step of reacting compound (13) with compound (14)
in the presence of an ammonium source to produce compound (15). The
compound (14) is known in the art or is easily obtained from a
compound known in the art.
The method for reacting an aldehyde with a 1,2-diketone in the
presence of an ammonium source to produce an imidazole is not
particularly limited as long as the method does not influence the
other parts of the compound. This method can be carried out
according to a method well known in the techniques of organic
synthetic chemistry, for example, a method described in J. Chen, Z.
Wang, C.-M. Li, Y. Lu, P. K. Vaddady, B. Meibohm, J. T. Dalton, D.
D. Miller and W. Li, Journal of Medicinal Chemistry, 53, 7414
(2010) or M. A. Toledo, C. Pedregal, C. Lafuente, N. Diaz, M. A.
Martinez-Grau, A. Jimenez, A. Benito, A. Torrado, C. Mateos, E. M.
Joshi, S. D. Kahl, K. S. Rash, D. R. Mudra, V. N. Barth, D. B.
Shaw, D. McKinzie, J. M. Witkin and M. A. Statnick, Journal of
Medicinal Chemistry, 57, 3418 (2014).
The ammonium source used is preferably ammonia or ammonium
acetate.
The solvent used is preferably an alcohol or a mixture of an
alcohol and water, and more preferably a mixture of methanol and
water or a mixture of isopropanol and water.
The reaction temperature is preferably 0 to 80.degree. C.
The reaction time is preferably 1 hour to 4 days.
(Step C-2)
Step C-2 is the step of reacting compound (15) obtained in the step
C-1 with compound (16) in the presence of a base to produce
compound (17). The compound (16) is known in the art or is easily
obtained from a compound known in the art.
Examples of the base used can include alkali metal carbonates,
alkali metal hydrides, lithium amides, and alkali metal
silylamides. The base is preferably an alkali metal carbonate, more
preferably potassium carbonate or cesium carbonate.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters,
nitriles, ketones, and amides. The solvent is preferably an amide,
more preferably N,N-dimethylformamide.
The reaction temperature is preferably 0.degree. C. to 80.degree.
C.
The reaction time is preferably 15 minutes to 24 hours.
(Step C-3)
Step C-3 is the step of cyclizing compound (17) obtained in the
step C-2 in the presence of a base to produce compound (18).
When L.sup.5 is a silyl group, the compound (18) can be produced
according to the Step B-3
When L.sup.5 is a hydrogen atom, the compound (18) can be produced
according to the Step A-2-1.
(Step C-4)
Step C-4 is the step of reacting the compound (18) obtained in the
step C-3 with compound (7) in the presence of a base to produce
compound (I).
When L.sup.1 is a nitro group, the compound (I) can be produced
according to the step A-4-1.
When L.sup.1 is an amino group, the compound (I) can be produced
according to the step A-4-1b.
When L.sup.1 is a halogeno group, the compound (I) can be produced
according to the step A-4-3.
(Step D-1)
Step D-1 is the step of condensing compound (19) with compound (20)
to produce compound (21). The compound (20) is known in the art or
is easily obtained from a compound known in the art.
The method for condensing a ketone with an acetal to produce
.alpha.,.beta.-unsaturated ketone is not particularly limited as
long as the method does not influence the other parts of the
compound. This method can be carried out according to a method well
known in the techniques of organic synthetic chemistry, for
example, a method described in D. W. Boykin, A. Kumar, M. Bajic, G.
Xiao, W. D. Wilson, B. C. Bender, D. R. McCurdy, J. E. Hall and R.
R. Tidwell, European Journal of Medicinal Chemistry, 32, 965 (1997)
or I. M. El-Deeb, M. Ibrahim and S. H. Lee, Bioorganic and
Medicinal Chemistry, 18, 3860(2010).
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, and
amides. Alternatively, the solvent may not be used. Preferably, the
solvent is not used.
The reaction temperature is preferably room temperature to
140.degree. C.
The reaction time is preferably 30 minutes to 12 hours.
(Step D-2)
Step D-2 is the step of reacting compound (21) obtained in the step
D-1 with compound (22) in the presence or absence of an additive to
produce compound (23). The compound (22) is known in the art or is
easily obtained from a compound known in the art. The compound (23)
of interest of this step can also be converted, if necessary, to
another compound (23) of interest through deprotection reaction.
The method for converting the obtained compound (23) of interest to
another compound (23) of interest by the removal of the protective
group differs depending on the type of the protective group and can
be generally carried out according to a routine method such as a
method well known in the techniques of organic synthetic chemistry,
for example, a method described in T. W. Greene, P. G. M. Wuts,
Protective Groups in Organic Synthesis Fifth Edition, 2014, John
Wiley & Sons, Inc.
Examples of the additive used can include: inorganic acids such as
hydrochloric acid; organic acids such as acetic acid,
trifluoroacetic acid; and organic sulfonic acids such as
methanesulfonic acid, p-toluenesulfonic acid; alkali metal
carbonates such as sodium carbonate, potassium carbonate, and
cesium carbonate; alkali metal bicarbonates such as sodium
bicarbonate; organic amines such as triethylamine,
diisopropylethylamine, N-methylmorpholine, pyridine, 2,6-lutidine.
Alternatively, the additive may not be used. The additive is
preferably an organic acid, more preferably acetic acid.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
water and mixtures thereof. The solvent is preferably an alcohol or
a mixture of an alcohol and water, more preferably ethanol or a
mixture of ethanol and water.
The reaction temperature is preferably room temperature to
90.degree. C.
The reaction time is preferably 1 hour to 24 hours.
(Step D-3)
Step D-3 is the step of cyclizing compound (23) obtained in the
step D-2 in the presence of a base to produce compound (24).
When L.sup.5 is a silyl group, the compound (24) can be produced
according to the Step B-3
When L.sup.5 is a hydrogen atom, the compound (24) can be produced
according to the Step A-2-1.
(Step D-4)
Step D-4 is the step of reacting the compound (24) obtained in the
step D-3 with compound (7) in the presence of a base to produce
compound (I).
When L.sup.1 is a nitro group, the compound (I) can be produced
according to the step A-4-1.
When L.sup.1 is an amino group, the compound (I) can be produced
according to the step A-4-1b.
When L.sup.1 is a halogeno group, the compound (I) can be produced
according to the step A-4-3.
(Step E-1)
Step E-1 is the step of reacting compound (1) with compound (25)
and compound (22) to produce compound (26). The compound (25) is
known in the art or is easily obtained from a compound known in the
art.
The method for reacting a carboxylic acid with a primary amidine
followed by reaction with a mono-substituted hydrazine to produce a
1,3,4-triazole is not particularly limited as long as the method
does not influence the other parts of the compound. For example,
this method can be carried out according to a method described in
G. M. Castanedo, P. S. Seng, N. Blaquiere and S. T. Staben, Journal
of Organic Chemistry, 76, 1177 (2011).
(Step E-2)
Step E-2 is the step of cyclizing compound (26) obtained in the
step E-2 in the presence of a base to produce compound (27).
When L.sup.5 is a silyl group, the compound (27) can be produced
according to the Step B-3
When L.sup.5 is a hydrogen atom, the compound (27) can be produced
according to the Step A-2-1.
(Step E-3)
Step E-3 is the step of reacting the compound (27) obtained in the
step E-2 with compound (7) in the presence of a base to produce
compound (I).
When L.sup.1 is a nitro group, the compound (I) can be produced
according to the step A-4-1.
When L.sup.1 is an amino group, the compound (I) can be produced
according to the step A-4-1b.
When L.sup.1 is a halogeno group, the compound (I) can be produced
according to the step A-4-3.
(Step F-1)
Step F-1 is the step of condensing compound (1) with compound (29)
to produce compound (30). The compound (1) and (29) are known in
the art or is easily obtained from a compound known in the art.
The method for condensing a carboxylic acid with an amine differs
depending on the type of the carboxylic acid and can be generally
carried out by a method well known in the techniques of organic
synthetic chemistry, for example, a method described in
Comprehensive Organic Transformations (Second Edition, 1999, John
Wiley & Sons, Inc., pp. 1929-1930, 1941-1949, and 1953-1954). A
preferred method involves converting the carboxylic acid to a
corresponding acid halide, which is then condensed with a
corresponding amine. Thus, step F-1 comprises:
(step F-1-1): the step of reacting compound (1) with a halogenating
agent; and
(step F-1-2): the step of reacting the compound obtained in the
step F-1-1 with compound (29) in the presence of a base.
(Step F-1-1)
Examples of the halogenating agent used can include: thionyl
chloride, phosphorus trichloride, phosphorus oxychloride,
phosphorus pentachloride, phosphorus tribromide, phosphorus
pentabromide, oxalyl chloride, carbon
tetrachloride-triphenylphosphine,
hexachloroethane-triphenylphosphine,
N-chlorosuccinimide-triphenylphosphine, carbon
tetrabromide-triphenylphosphine, and
N-bromosuccinimide-triphenylphosphine; and combinations of these
halogenating agents with additives such as N,N-dimethylformamide.
The halogenating agent is preferably a combination of thionyl
chloride with an additive or a combination of oxalyl chloride with
an additive, more preferably a combination of oxalyl chloride with
N,N-dimethylformamide.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, and
esters. The solvent is preferably a halogenated hydrocarbon or an
ether, more preferably methylene chloride or tetrahydrofuran.
The reaction temperature is preferably 0.degree. C. to 100.degree.
C., more preferably room temperature.
The reaction time is preferably 15 minutes to 6 hours.
(Step F-1-2)
Examples of the base used can include alkali metal carbonates,
alkali metal bicarbonates, alkali metal hydrides, lithium amides,
alkali metal silylamides, alkyllithiums, and organic amines. The
base is preferably an organic amine, more preferably triethylamine
or diisopropylethylamine.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters,
and amides. The solvent is preferably an ether or an amide, more
preferably tetrahydrofuran or N,N-dimethylformamide.
The reaction temperature is preferably -78.degree. C. to
100.degree. C., more preferably -20.degree. C. to room
temperature.
The reaction time is preferably 15 minutes to 24 hours.
(Step F-2)
Step F-2 is the step of intramolecularly cyclizing the compound
(30) obtained in the step F-1-2 in the presence of a base to
produce compound (31). The compound (31) of interest of this step
can also be converted, if necessary, to another compound (31) of
interest through chemical modification. The method for converting
the obtained compound (31) of interest to another compound (31) of
interest differs depending on the type of the functional group and
can be generally carried out according to a routine method such as
a method well known in the techniques of organic synthetic
chemistry, for example, a method described in Comprehensive Organic
Transformations, Second Edition, 1999, John Wiley & Sons,
Inc.
Examples of the base used can include alkali metal carbonates,
alkali metal bicarbonates, alkali metal hydrides, alkali metal
hydroxides, alkaline earth metal hydroxides, alkali metal
alkoxides, lithium amides, alkali metal silylamides, and organic
amines. The base is preferably an alkali metal hydride, an alkali
metal carbonate, an alkali metal silylamide, or an organic amine,
more preferably sodium bistrimethylsilylamide, sodium hydride,
potassium carbonate, or cesium carbonate.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, and amides. The solvent is preferably an
ether, a nitrile, or an amide, more preferably tetrahydrofuran,
acetonitrile, or N,N-dimethylformamide.
The reaction temperature is preferably -78.degree. C. to
100.degree. C.
The reaction time is preferably 15 minutes to 24 hours.
(Step F-3)
Step F-3 is the step of reacting the compound (31) obtained in the
step F-2 with compound (32) in the presence of a base to produce
compound (I). The compound (32) is known in the art or is easily
obtained from a compound known in the art.
Hereinafter, this step is referred to as step F-3-1 when L.sup.1 is
a nitro group, as step F-3-2 when L.sup.1 is an amino group, and as
step F-3-3 when L.sup.1 is a halogeno group.
(Step F-3-1)
When L.sup.1 is a nitro group, step F-3-1 comprises:
(step F-3-1a): the step of selectively reducing the nitro group of
the compound obtained in the step F-2 into an amino group; and
(step F-3-1b): the step of reacting the compound obtained in the
step F-3-1a with compound (32) in the presence of a base to produce
compound (I).
(Step F-3-1a)
The method for selectively reducing the nitro group is not
particularly limited as long as the method does not influence the
other parts of the compound. This method can be generally carried
out by a method well known in the techniques of organic synthetic
chemistry, for example, a method described in Comprehensive Organic
Transformations (Second Edition, 1999, John Wiley & Sons, Inc.,
pp. 821-828). The method is preferably a catalytic reduction method
or a method using a combination of a reducing agent and an
additive.
Examples of the metal catalyst for use in the catalytic reduction
method can include: palladium catalysts such as palladium on
carbon, palladium black, palladium hydroxide on carbon, and
palladium on barium sulfate; platinum catalysts such as platinum
oxide and platinum black, platinium on carbon; rhodium catalysts
such as rhodium on aluminum oxide and
chlorotris(triphenylphosphine)rhodium (I); and nickel catalysts
such as Raney nickel. The metal catalyst is preferably a palladium
catalyst, more preferably 10% palladium on carbon.
The hydrogen pressure in the catalytic reduction method is
preferably 1 to 10 atm, more preferably 1 atm.
The solvent for use in the catalytic reduction method is not
particularly limited as long as the solvent is inert to this
reaction. Examples thereof can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, amides, and mixtures thereof. The
solvent is preferably an alcohol, an ether, an amide, or a mixture
thereof, more preferably methanol or a mixture of tetrahydrofuran
and ethanol.
The reaction temperature in the catalytic reduction method is
preferably room temperature to 60.degree. C.
The reaction time in the catalytic reduction method is preferably 1
hour to 24 hours.
The combination of the reagents for use in the reaction using the
combination of the reducing agent and the additive is preferably a
combination of sodium borohydride and nickel(II) chloride
hexahydrate, a combination of zinc powder and acetic acid, a
combination of iron powder and acetic acid, or a combination of
tin(II) chloride and hydrochloric acid, more preferably a
combination of sodium borohydride and nickel(II) chloride
hexahydrate.
The solvent for use in the reaction using the combination of the
reducing agent and the additive is preferably a mixture of an
alcohol and an ether, more preferably a mixture of tetrahydrofuran
and methanol.
The reaction temperature in the reaction using the combination of
the reducing agent and the additive is preferably 0.degree. C. to
room temperature.
The reaction time in the reaction using the combination of the
reducing agent and the additive is preferably 5 minutes to 2
hours.
(Step F-3-1b)
Examples of the base used can include alkali metal carbonates,
alkali metal bicarbonates, alkali metal hydrides, alkali metal
hydroxides, alkali metal alkoxides, lithium amides, alkali metal
silylamides, and organic amines. The base is preferably an organic
amine, more preferably pyridine.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters,
nitriles, ketones, and amides. Alternatively, the solvent may not
be used. Preferably, the solvent is not used.
The reaction temperature is preferably 0.degree. C. to 100.degree.
C., more preferably room temperature to 80.degree. C.
The reaction time is preferably 5 minutes to 24 hours, more
preferably 15 minutes to 3 hours.
The reaction for converting the obtained compound (I) of interest
obtained in this step to another compound (I) of interest by the
removal of the protective group is not particularly limited as long
as the reaction does not influence the other parts of the compound.
This reaction can be carried out according to a routine method, for
example, a method described in T. W. Greene, P. G. M. Wuts,
Protective Groups in Organic Synthesis, Fifth Edition, 2014, John
Wiley & Sons, Inc.
(Step F-3-2)
When L.sup.1 is an amino group, the compound (I) can be produced
according to the step F-3-1b.
(Step F-3-3)
When L.sup.1 is a halogeno group, step F-3-3 comprises:
(step F-3-3a): the step of converting the bromo group of the
compound produced in the step F-2 to a N-Boc amide group using a
metal catalyst in the presence of a base;
(step F-3-3b): the step of deprotecting the N-Boc group of the
compound obtained in the step F-3-3a to form an amino group;
and
(step F-3-3c): the step of reacting the compound obtained in the
step F-3-3b with compound (32) in the presence of a base to produce
compound (I).
(Step F-3-3a)
The method for converting the bromo group on the aromatic ring to a
N-Boc amide group is not particularly limited as long as the method
does not influence the other parts of the compound. This method can
be carried out according to a method well known in the techniques
of organic synthetic chemistry, for example, a method described in
A. P. Dishington, P. D. Johnson, J. G. Kettle, Tetrahedron Letters,
45, 3733 (2004) or S. Bhagwanth, A. G. Waterson, G. M. Adjabeng, K.
R. Hornberger, Journal of Organic Chemistry, 74, 4634 (2009)
The metal catalyst used is preferably a combination of
tris(dibenzylideneacetone)dipalladium(0) chloroform complex and
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos.TM.) or a
combination of tris(dibenzylideneacetone)dipalladium(0) chloroform
complex and
di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine
(tBuXPhos.TM.).
The base used is preferably an alkali metal carbonate, an alkali
metal phosphate, or an alkali metal alkoxide, and more preferably
potassium carbonate, cesium carbonate, potassium phosphate, or
sodium tert-butoxide.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, amides, and mixtures thereof. The
solvent is preferably an aromatic hydrocarbon, an ether, a nitrile,
or an amide, more preferably toluene, 1,4-dioxane, acetonitrile, or
N,N-dimethylformamide.
The reaction temperature is preferably room temperature to
100.degree. C.
The reaction time is preferably 1 hour to 48 hours.
(Step F-3-3b)
The method for deprotecting the N-Boc group is not particularly
limited as long as the method does not influence the other parts of
the compound. This method can be carried out according to a routine
method, for example, a method described in T. W. Greene, P. G. M.
Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014,
John Wiley & Sons, Inc., pp. 930-946.
(Step F-3-3c)
The compound (I) can be produced according to the step F-3-1b.
When L.sup.1 is a bromo group, the compound (I) can also be
produced through the reaction of the compound (31) with the
compound (32) using a metal catalyst in the presence of a base.
The method for converting the bromo group on the aromatic ring to
an arylsulfonamide group is not particularly limited as long as the
method does not influence the other parts of the compound. This
method can be carried out according to a method well known in the
techniques of organic synthetic chemistry, for example, a method
described in X. Wang, A. Guram, M. Ronk, J. E. Milne, J. S. Tedrow
and M. M. Faul, Tetrahedron Letters, 53, 7 (2012), W. Deng, L. Liu,
C. Zhang, M. Liu, and Q.-X. Guo, Tetrahedron Letters, 46, 7295
(2005), or D. K. Luci, J. B. Jameson, A. Yasgar, G. Diaz, N. Joshi,
A. Kantz, K. Markham, S. Perry, N. Kuhn, J. Yeung, E. H. Kerns, L.
Schultz, M. Holinstat, J. Nadler, D. A. Taylor-Fishwick, A. Jadhav,
A. Simeonov, T. R. Holman and D. J. Maloney, Journal of Medicinal
Chemistry, 57, 495 (2014).
The metal catalyst used is preferably a combination of copper(I)
iodide and N-methyl-2-(methylamino)ethylamine, or a combination of
copper(I) iodide and
trans-N,N'-dimethylcyclohexane-1,2-diamine.
The base used is preferably an alkali metal carbonate, an alkali
metal phosphate, or an alkali metal alkoxide, more preferably
potassium carbonate, cesium carbonate, or potassium phosphate.
Examples of the solvent used can include aliphatic hydrocarbons,
aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers,
esters, nitriles, ketones, amides, and mixtures thereof. The
solvent is preferably an aromatic hydrocarbon, an ether, a nitrile,
or an amide, more preferably xylene, 1,4-dioxane, acetonitrile, or
N,N-dimethylformamide.
The reaction temperature is preferably room temperature to
100.degree. C.
The reaction time is preferably 1 hour to 48 hours.
When A is represented by the general formula (IIg) and (IIh), the
compound represented by the general formula (I) of the present
invention can be produced according to the methods A-F.
When the compound represented by the general formula (I) of the
present invention or the pharmacologically acceptable salt thereof
is used as a pharmaceutical, the compound or the salt can be
administered alone (i.e., as a bulk) or can be administered orally
as an appropriate pharmaceutically acceptable preparation such as a
tablet, a capsule, granules, a powder, or a syrup or parenterally
as an appropriate pharmaceutically acceptable preparation such as
an injection, a suppository, or a patch (preferably orally).
These preparations are produced by well-known methods using
additives such as excipients, binders, disintegrants, lubricants,
emulsifiers, stabilizers, corrigents, diluents, solvents for
injections, oleaginous bases, and water-soluble bases.
Examples of the excipients can include organic excipients and
inorganic excipients. Examples of the organic excipients can
include: sugar derivatives such as lactose, saccharose, glucose,
mannitol, and sorbitol; starch derivatives such as corn starch,
potato starch, .alpha.-starch, dextrin, and carboxymethyl starch;
cellulose derivatives such as crystalline cellulose,
low-substituted hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose,
carboxymethylcellulose calcium, and internally cross-linked
carboxymethylcellulose sodium; gum arabic; dextran; and pullulan.
Examples of the inorganic excipients can include: light anhydrous
silicic acid and silicate derivatives such as synthetic aluminum
silicate and calcium silicate; phosphates such as calcium
phosphate; and sulfates such as calcium sulfates.
Examples of the binders can include: the excipients listed above;
gelatin; polyvinylpyrrolidone; and polyethylene glycol.
Examples of the disintegrants can include: the excipients listed
above; chemically modified starch or cellulose derivatives such as
croscarmellose sodium and carboxymethyl starch sodium; and
cross-linked polyvinylpyrrolidone.
Examples of the lubricants can include: talc; stearic acid; stearic
acid metal salts such as calcium stearate and magnesium stearate;
colloidal silica; waxes such as bees wax and spermaceti; boric
acid; glycol; D,L-leucine; carboxylic acids such as fumaric acid
and adipic acid; carboxylic acid sodium salts such as sodium
benzoate; sulfates such as sodium sulfate; lauryl sulfates such as
sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids
such as silicic anhydride and silicic acid hydrate; and the starch
derivatives listed as the excipients.
Examples of the emulsifiers can include: colloidal clay such as
bentonite and veegum; anionic surfactants such as sodium lauryl
sulfate and calcium stearate; cationic surfactants such as
benzalkonium chloride; and nonionic surfactants such as
polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid
ester, and sucrose fatty acid ester.
Examples of the stabilizers can include: p-hydroxybenzoic acid
esters such as methylparaben and propylparaben; alcohols such as
chlorobutanol, benzyl alcohol, and phenylethyl alcohol;
benzalkonium chloride; phenols such as phenol and cresol;
thimerosal; dehydroacetic acid; and sorbic acid.
Examples of the corrigents can include sweeteners, acidulants, and
flavors usually used.
Examples of the diluents can include water, ethanol, propylene
glycol, ethoxylated isostearyl alcohol, and polyoxyethylene
sorbitan fatty acid esters.
Examples of the solvents for injections can include water, ethanol,
and glycerin.
Examples of the oleaginous bases can include cacao butter, laurin
butter, coconut oil, palm kernel oil, Camellia oil, liquid
paraffin, white petrolatum, purified lanoline, glycerin
monostearate, polyoxyethylene hydrogenated castor oil, sorbitan
fatty acid ester, sucrose fatty acid ester, stearyl alcohol, and
cetanol.
Examples of the water-soluble bases can include glycerin,
polyethylene glycol, ethanol, and purified water.
The dose of the compound represented by the general formula (I) of
the present invention or the pharmacologically acceptable salt
thereof serving as an active ingredient differs depending on the
symptoms and age of a patient, etc. The single dose thereof is
0.001 mg/kg (preferably 0.01 mg/kg) as the lower limit and 10 mg/kg
(preferably 1 mg/kg) as the upper limit for oral administration and
0.001 mg/kg (preferably 0.01 mg/kg) as the lower limit and 10 mg/kg
(preferably 1 mg/kg) as the upper limit for parenteral
administration and can be administered once to six times a day
according to the symptoms.
The compound of the present invention can be used in combination
with any of various therapeutic or prophylactic agents for the
aforementioned disease for which the compound of the present
invention is probably effective. In this combined use, the compound
of the present invention and the agent may be administered
simultaneously, separately but continuously, or at the desired time
interval. The preparations to be administered simultaneously may be
formulated as a combination drug or formulated as separate
preparations.
The sulfonamide compound or the pharmacologically acceptable salt
thereof, which is the compound of the present invention, has an
excellent TNAP inhibitory effect and is useful as a therapeutic or
prophylactic agent for pseudoxanthoma elasticum (PXE), generalized
arterial calcification of infancy (GACI), craniometaphyseal
dysplasia (CMD), ossification of the yellow ligament (OYL),
arterial calcification due to deficiency of CD73 (ACDC), arthrosis
deformans, osteoarthritis, ankylosis of the joint, idiopathic
infantile arterial calcification (IIAC), ankylosing spondylitis
(AS), tumoral calcinosis (TC), progressive osseous heteroplasia
(POH), Keutel syndrome, vascular calcification associated with
chronic renal failure (including glomerulonephritis, IgA
nephropathy, hypertensive nephropathy, and diabetic nephropathy)
and secondary parathyroid hyperplasia, metastatic calcification,
calciphylaxis, calcific tendinitis of the longus colli muscle,
fibrodysplasia ossificans progressiva (FOP), calcific aortic
stenosis, pericarditis calculosa, atherosclerotic vascular
calcification, calcific uremic arteriopathy (CUA), Kawasaki
disease, calcification due to obesity and aging, tibial arterial
calcification, bone metastasis, prosthetic calcification, Paget's
disease, or peritoneal calcification. Moreover, the compound of the
present invention has low toxicity and excellent safety and as
such, is very useful as a pharmaceutical.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Hereinafter, the present invention will be described in more detail
with reference to Examples, etc. However, the scope of the present
invention is not intended to be limited by them.
The chemical structural formulas described in Examples represent
the chemical structures of corresponding compounds in a free
form.
Elution in column chromatography in Examples was carried out under
observation by thin layer chromatography (TLC). In the TLC
observation, silica gel 60F.sub.254 manufactured by Merck KGaA was
used as a TLC plate; a solvent used as an eluting solvent in column
chromatography was used as a developing solvent; and a UV detector
or a chromogenic method using a coloring agent (e.g., a ninhydrin
coloring solution, an anisaldehyde coloring solution, an ammonium
phosphomolybdate coloring solution, a cerium ammonium nitrate (CAM)
coloring solution, or an alkaline permanganate coloring solution)
was used as a detection method. Silica gel SK-85 (230-400 mesh)
also manufactured by Merck KGaA, silica gel 60 N (40-50 .mu.m)
manufactured by Kanto Chemical Co., Inc., or Chromatorex NH
(200-350 mesh) manufactured by Fuji Silysia Chemical Ltd. was used
as silica gel for columns. In addition to general column
chromatography, an automatic chromatography apparatus
(Purif-.alpha.2 or Purif-espoir2) manufactured by Shoko Scientific
Co., Ltd., an automatic chromatography apparatus (W-Prep 2XY)
manufactured by Yamazen Corp., an automatic chromatography
apparatus (Isolera One) manufactured by Biotage Japan Ltd., or an
automatic chromatography apparatus (CombiFlash Rf) manufactured by
Teledyne Isco, Inc. was appropriately used. The eluting solvent was
determined on the basis of the TLC observation.
In Examples, nuclear magnetic resonance (.sup.1H NMR) spectra were
indicated by chemical shift .delta. values (ppm) determined with
tetramethylsilane as a standard. Splitting patterns were indicated
by s for singlet, d for doublet, t for triplet, q for quartet, m
for multiplet, and br for broad. Mass spectrometry (hereinafter,
referred to as MS) was conducted by the electron ionization (EI),
electron spray ionization (ESI), atmospheric pressure chemical
ionization (APCI), electron spray atmospheric pressure chemical
ionization (ES/APCI), or fast atom bombardment (FAB) method.
In each step of Examples, the adjustment of a reaction solution and
reaction were carried out at room temperature unless the
temperature is otherwise specified.
EXAMPLES
(Example 1)
5-chloro-2-methoxy-N-(3-methyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,-
3-d][1,4]oxazepin-10-yl)benzenesulfonamide
##STR00018##
(1a) 2-[(2,4-Dimethoxybenzyl)amino]ethanol
To a mixture of 2,4-dimethoxybenzaldehyde (16.20 g, 97.5 mmol) and
2-aminoethanol (5.98 g, 97.9 mmol) in methanol (120 mL), anhydrous
sodium sulfate (6.23 g, 43.9 mmol) was added, and the mixture was
stirred at room temperature for 20 hours. Subsequently, to the
mixture, sodium borohydride (1.84 g, 48.6 mmol) was added over 15
minutes, and the mixture was stirred at 22.degree. C. for 30
minutes. To the reaction mixture, acetic acid (2.8 mL, 49 mmol) was
added, and the mixture was stirred for 10 minutes and concentrated
into approximately 1/2 of the amount under reduced pressure. The
concentrated mixture was diluted by addition of water and a
saturated aqueous solution of sodium bicarbonate, followed by
extraction with methylene chloride. The organic layer was washed
with a saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure. To the residue, n-hexane (100
mL) and ethyl acetate (4 mL) were added, and the precipitated solid
was collected by filtration, washed with n-hexane, and then dried
to obtain the title compound (18.44 g, yield: 90%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.12 (1H, d,
J=8.2 Hz), 6.47-6.42 (2H, m), 3.82 (3H, s), 3.80 (3H, s), 3.74 (2H,
S), 3.65-3.63 (2H, m), 2.76-2.74 (2H, m).
(1b)
2-Chloro-N-(2,4-dimethoxybenzyl)-N-(2-hydroxyethyl)-5-nitropyridine-3-
-carboxamide
To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (4.91
g, 24.2 mmol) and oxalyl chloride (2.6 mL, 30 mmol) in methylene
chloride (120 mL), N,N-dimethylformamide (0.10 mL, 1.3 mmol) was
added at room temperature, and the mixture was stirred at the same
temperature as above for 30 minutes. The reaction mixture was
concentrated under reduced pressure to prepare a crude product of
2-chloro-5-nitropyridine-3-carboxylic acid chloride. To a solution
of 2-[(2,4-dimethoxybenzyl)amino]ethanol (5.11 g, 24.2 mmol)
obtained in Example (1a) and N,N-diisopropylethylamine (8.25 mL,
48.5 mmol) in tetrahydrofuran (50 mL), a solution of the crude
product of 2-chloro-5-nitropyridine-3-carboxylic acid chloride in
tetrahydrofuran (70 mL) was added over 20 minutes under ice
cooling, and the reaction mixture was stirred at the same
temperature as above for 90 minutes. To the reaction mixture, water
(0.05 mL) was added, and then, the mixture was concentrated under
reduced pressure. The concentrated mixture was diluted by addition
of water, followed by extraction with ethyl acetate. The organic
layer was washed with water and a saturated aqueous solution of
sodium chloride, and anhydrous magnesium sulfate and charcoal were
added thereto. After filtration through pad of Celite 545 .RTM.,
the solvent was distilled off under reduced pressure. To the
residue, diisopropyl ether (50 mL) and ethyl acetate (10 mL) were
added to precipitate a solid. The suspension was stirred at room
temperature for 30 minutes. The precipitated solid was collected by
filtration, washed with a mixed solvent of diisopropyl ether/ethyl
acetate=5/1, and then dried to obtain the title compound (8.30 g,
yield: 87%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.24 (0.8H, d,
J=2.7 Hz), 9.21 (0.2H, d, J=2.7 Hz), 8.57 (0.2H, d, J=2.7 Hz), 8.44
(0.8H, d, J=2.7 Hz), 7.38 (0.2H, d, J=8.2 Hz), 6.99 (0.8H, d, J=8.2
Hz), 6.54-6.48 (0.4H, m), 6.45-6.40 (1.6H, m), 5.13 (0.2H, d,
J=14.9 Hz), 4.53 (0.2H, d, J=14.9 Hz), 4.38-3.54 (10.8H, m),
3.24-3.19 (0.4H, t, J=5.1 Hz), 2.42 (0.4H, t, J=5.1 Hz).
(1c)
4-(2,4-Dimethoxybenzyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-
-5(2H)-one
A solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran
(ca. 1.9 mol/L, 14.4 mL, 27.4 mmol) was diluted with
tetrahydrofuran (450 mL). A solution of
2-chloro-N-(2,4-dimethoxybenzyl)-N-(2-hydroxyethyl)-5-nitropyridine-3-car-
boxamide (7.22 g, 18.2 mmol) obtained in Example (1b) in
tetrahydrofuran (450 mL) was added thereto over 70 minutes under
ice cooling, and the mixture was stirred at the same temperature as
above for 10 minutes and further stirred at room temperature for 30
minutes. To the reaction mixture, a saturated aqueous solution of
ammonium chloride (100 mL) was added, and then, the reaction
mixture was concentrated into approximately 1/5 of the amount under
reduced pressure. The concentrated mixture was diluted by addition
of water, followed by extraction with ethyl acetate twice. The
organic layer was washed with water and a saturated aqueous
solution of sodium chloride and dried over anhydrous magnesium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified by silica gel column
chromatography (ethyl acetate/n-hexane/methylene
chloride=1/1/1-3/2/2). To the obtained solid, diisopropyl ether (20
mL) and ethyl acetate (10 mL) were added, and the suspension was
stirred at room temperature for overnight. The precipitated solid
was collected by filtration, washed with a mixed solvent of
diisopropyl ether/ethyl acetate=2/1, and then dried to obtain the
title compound (4.18 g, yield: 64%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.34 (1H, d,
J=2.7 Hz), 9.20 (1H, d, J=2.7 Hz), 7.34-7.32 (1H, m), 6.50-6.48
(2H, m), 4.76 (2H, s), 4.53-4.51 (2H, m), 3.84 (3H, s), 3.81 (3H,
s), 3.78-3.76 (2H, m).
(1d) 7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepine-5
(2H)-thione
To a solution of
4-(2,4-Dimethoxybenzyl)-7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2-
H)-one (2.4261 g, 6.75 mmol) obtained in Example (1c) and anisole
(1.48 mL, 13.6 mmol) in chloroform (50 mL), trifluoroacetic acid
(15 mL) and trifluoromethanesulfonic acid (1.78 mL, 20.3 mmol) were
added, and the mixture was stirred at room temperature for 3 hour.
The reaction mixture was concentrated under reduced pressure, and
the concentrated mixture was diluted by addition of chloroform and
a saturated aqueous solution of sodium bicarbonate, and the mixture
was stirred at room temperature for further 30 minutes. A
participated solid was collected by filtration to obtain a crude
solid. The filtrate was extracted with chloroform and the organic
layer dried over anhydrous sodium sulfate. After filtration, the
solvent was distilled off under reduced pressure. The residue was
combined with the above crude solid, diisopropyl ether was added
thereto, and the precipitated solid was collected by filtration
again, washed with diisopropyl ether, and then dried to obtain
7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (971.1 mg,
yield: 69%). To a suspension of
7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (667 mg,
3.19 mmol) obtained in the above step in tetrahydrofuran (30 mL)
was added Lawesson's reagent (785 mg, 1.94 mmol) at room
temperature and the mixture was stirred at 50.degree. C. for 3
hours in an oil bath. The reaction mixture was cooled and then
concentrated under reduced pressure. The residue was suspended by
addition of diisopropyl ether, and the suspension was stirred at
room temperature for 3 hours. The precipitated solid was collected
by filtration to obtain the title compound (630.5 mg). The filtrate
was concentrated under reduced pressure, and the residue was
purified in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-0/100) to obtain the title compound (254.7 mg; total:
885.2 mg, yield: quantitative).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.48 (1H, t,
J=2.4 Hz), 9.23 (1H, d, J=2.4 Hz), 8.70 (1H, br s), 4.78 (2H, t,
J=4.6 Hz), 3.86-3.73 (3H, m).
(1e)
5-(methylsulfanyl)-7-nitro-2,3-dihydropyrido[3,2-f][1,4]oxazepine
To a solution of
7-nitro-3,4-dihydropyrido[3,2-f][1,4]oxazepine-5(2H)-thione (215
mg, 1.11 mmol) obtained in Example (1d) in tetrahydrofuran (15 mL)
was added Sodium hydride (63% content, 73 mg, 1.92 mmol) under ice
cooling, and the mixture was stirred at the same temperature as
above for 15 minutes. Iodomethane (0.139 mL, 2.23 mmol) was added
thereto under ice cooling, and the mixture was stirred at room
temperature for 40 minutes. The mixture was cooled in ice water
bath, and diluted by addition of a saturated aqueous solution of
sodium chloride, followed by extraction with ethyl acetate. The
organic layer was washed with a saturated aqueous solution of
sodium chloride, and dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (n-hexane/ethyl acetate=100/0-50/50) to obtain the title
compound (107.0 mg, yield: 40%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.20 (1H, d,
J=3.0 Hz), 8.96 (1H, d, J=3.0 Hz), 4.75 (2H, t, J=4.3 Hz), 4.09
(2H, t, J=4.3 Hz), 2.48 (3H, s).
(1f)
3-methyl-10-nitro-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]-
oxazepine
To a suspension of
5-(methylsulfanyl)-7-nitro-2,3-dihydropyrido[3,2-f][1,4]oxazepine
(107.0 mg, 0.45 mmol) obtained in Example (1e) in ethanol (15 mL)
was added acetohydrazide (134 mg, 1.81 mmol) at room temperature,
and the mixture was heated to reflux for 23.5 hours in an oil bath.
The reaction mixture was cooled and then concentrated under reduced
pressure. The precipitated solid was collected by filtration,
washed with minimum volume of ethanol to obtain the title compound
(50.9 mg). The filtrate was concentrated under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (ethyl acetate/methanol=100/0-75/25) to obtain the title
compound (34.1 mg; total: 85.0 mg, yield: 77%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 9.45 (1H, d, J=2.4
Hz), 9.13 (1H, d, J=2.4 Hz), 4.76-4.74 (3H, m), 4.45-4.43 (3H, m),
2.45 (5H, s).
(1g)
3-methyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]oxazepin--
10-amine
To a mixture of
3-methyl-10-nitro-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]oxaz-
epine (85.0 mg, 0.34 mmol) obtained in Example (1f) in
tetrahydrofuran (2 mL) and methanol (2 mL), nickel(II) chloride
hexahydrate (164 mg, 0.69 mmol) was added. Subsequently, the
mixture was cooled in an ice water bath. Sodium borohydride (56 mg,
1.48 mmol) was added thereto, the mixture was stirred at room
temperature for 30 minutes. The reaction mixture was diluted by
addition of acetone and a saturated aqueous solution of sodium
bicarbonate, further Celite 545.RTM. (approximately 0.3 g) was
added thereto, and the mixture was stirred at room temperature for
further 30 minutes. The reaction mixture was filtered, and the
filtrate was concentrated under reduced pressure. The residue was
purified by reverse-phase silica gel column chromatography
(Chromatorex ODS 100-200 mesh, water/methanol=100/0-70/30) to
obtain the title compound (67.1 mg, yield: 90%).
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 8.10 (1H, br d,
J=2.4 Hz), 7.73 (1H, br d, J=2.4 Hz), 4.53 (2H, t, J=4.3 Hz), 4.37
(2H, t, J=4.3 Hz), 2.50 (3H, s).
(1h)
5-chloro-2-methoxy-N-(3-methyl-5,6-dihydropyrido[3,2-f][1,2,4]triazol-
o[4,3-d][1,4]oxazepin-10-yl)benzenesulfonamide
To a mixture of
3-methyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]oxazepin-10-a-
mine (67.1 mg, 0.31 mmol) obtained in Example (1g) and pyridine (2
mL, 25 mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (84 mg,
0.35 mmol) was added, and the mixture was stirred at 80.degree. C.
for 1.5 hours in an oil bath. The reaction mixture was cooled, and
then concentrated under reduced pressure. The residue was diluted
by addition of a 1N hydrochloric acid (1 mL) and purified by
reverse-phase silica gel column chromatography (Chromatorex ODS
100-200 mesh,
water/methanol/chloroform=100/0/0-50/50/0-0/100/0-0/50/50) to
obtain the title compound (49.1 mg, yield: 38%).
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.39 (1H,
s), 8.58 (1H, d, J=2.4 Hz), 8.02 (1H, d, J=2.4 Hz), 7.67-7.64 (2H,
m), 7.26 (1H, d, J=9.1 Hz), 4.50-4.49 (2H, m), 4.30-4.28 (2H, m),
3.90 (3H, s), 2.39 (3H, s).
MS spectrum (ES/APCI.sup.+): 422 (M+H), 424 (M+2+H).
(Example 2) Potassium
[(5-chloro-2-methoxyphenyl)sulfonyl](3-methyl-5,6-dihydropyrido[3,2-f][1,-
2,4]triazolo[4,3-d][1,4]oxazepin-10-yl)azanide (Potassium Salt of
Example 1)
##STR00019##
To a suspension of
5-chloro-2-methoxy-N-(3-methyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,-
3-d][1,4]oxazepin-10-yl)benzenesulfonamide (33.5 mg, 0.079 mmol)
obtained in Example (1h) in ethanol (1 mL), a solution of 0.5 N
potassium hydroxide in ethanol (0.174 mL, 0.087 mmol) was added at
room temperature, and the mixture was stirred at room temperature
for 29 hours.
The precipitated solid was collected by filtration, and then dried
to obtain the title compound (23.1 mg, yield: 63%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 8.25 (1H, d, J=2.4
Hz), 7.67-7.65 (2H, m), 7.34-7.32 (1H, m), 6.99 (1H, br d, J=9.1
Hz), 4.37-4.36 (2H, m), 4.23-4.22 (2H, m), 3.67 (3H, s), 2.37 (3H,
s).
(Example 3)
5-chloro-N-(3-ethyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]ox-
azepin-10-yl)-2-methoxybenzenesulfonamide
##STR00020##
(3a)
3-ethyl-10-nitro-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]o-
xazepine
The title compound (140.1 mg, yield: quantitative) was obtained by
production according to the method described in Examples (1f) using
5-(methylsulfanyl)-7-nitro-2,3-dihydropyrido[3,2-f][1,4]oxazepine
(120 mg, 0.50 mmol) obtained in Example (1e) and propanoic acid
hydrazide (90 mg, 1.02 mmol) as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.46 (1H, d,
J=3.0 Hz), 9.13 (1H, d, J=3.0 Hz), 4.76-4.74 (2H, m), 4.46-4.45
(2H, m), 2.81 (2H, q, J=7.5 Hz), 1.30 (3H, t, J=7.5 Hz).
(3b)
5-chloro-N-(3-ethyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,-
4]oxazepin-10-yl)-2-methoxybenzenesulfonamide
The title compound (28.4 mg, yield for 2 steps: 26%) was obtained
by production according to the method described in Examples (1g)
and (1h) using
3-ethyl-10-nitro-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4-
]oxazepine (131 mg, 0.50 mmol) obtained in Example (3a) and
5-chloro-2-methoxybenzenesulfonyl chloride (62.5 mg, 0.26 mmol) as
starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.00-8.97 (1H,
m), 8.41 (1H, t, J=3.0 Hz), 7.82 (1H, t, J=3.0 Hz), 7.42 (1H, dd,
J=9.1, 2.4 Hz), 6.93-6.91 (1H, m), 4.55-4.54 (2H, m), 4.29-4.28
(2H, m), 3.95-3.92 (3H, m), 2.91-2.87 (2H, m), 1.43 (3H, t, J=7.6
Hz).
MS spectrum (ES/APCI.sup.+): 436 (M+H), 438 (M+2+H).
(Example 4) Potassium
[(5-chloro-2-methoxyphenyl)sulfonyl](3-ethyl-5,6-dihydropyrido[3,2-f][1,2-
,4]triazolo[4,3-d][1,4]oxazepin-10-yl)azanide (Potassium Salt of
Example 3)
##STR00021##
The title compound (16.7 mg, yield: 70%) was obtained by production
according to the method described in Example 2 using
5-chloro-N-(3-ethyl-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3-d][1,4]ox-
azepin-10-yl)-2-methoxybenzenesulfonamide (22 mg, 0.050 mmol)
obtained in Example (3b) and a solution of 0.5 N potassium
hydroxide in ethanol (0.11 mL, 0.055 mmol).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 8.26 (1H, s),
7.68-7.67 (2H, m), 7.35-7.33 (1H, m), 7.00 (1H, br d, J=8.5 Hz),
4.38-4.37 (2H, m), 4.25-4.24 (2H, m), 3.68 (3H, s), 2.73 (2H, q,
J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz).
(Example 5)
5-chloro-2-methoxy-N-[3-(propan-2-yl)-5,6-dihydropyrido[3,2-f][1,2,4]tria-
zolo[4,3-d][1,4]oxazepin-10-yl]benzenesulfonamide
##STR00022##
(5a)
10-nitro-3-(propan-2-yl)-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,3--
d][1,4]oxazepine
The title compound (61.2 mg, yield: 44%) was obtained by production
according to the method described in Examples (1f) using
5-(methylsulfanyl)-7-nitro-2,3-dihydropyrido[3,2-f][1,4]oxazepine
(120 mg, 0.50 mmol) obtained in Example (1e) and isobutyrohydrazide
(111 mg, 1.09 mmol) as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.46 (1H, d,
J=3.0 Hz), 9.13 (1H, d, J=3.0 Hz), 4.76-4.74 (2H, m), 4.51-4.50
(2H, m), 3.21-3.15 (1H, m), 1.31 (6H, d, J=6.7 Hz).
(5b)
5-chloro-2-methoxy-N-[3-(propan-2-yl)-5,6-dihydropyrido[3,2-f][1,2,4]-
triazolo[4,3-d][1,4]oxazepin-10-yl]benzenesulfonamide
The title compound (41.2 mg, yield for 2 steps: 41%) was obtained
by production according to the method described in Examples (1g)
and (1g) using
10-nitro-3-(propan-2-yl)-5,6-dihydropyrido[3,2-f][1,2,4]triazolo[4,-
3-d][1,4]oxazepine (61.2 mg, 0.22 mmol) obtained in Example (5a)
and 5-chloro-2-methoxybenzenesulfonyl chloride (60.8 mg, 0.25 mmol)
as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.74-8.72 (1H,
m), 8.39-8.38 (1H, m), 7.75-7.75 (1H, m), 7.43 (1H, dd, J=8.5, 2.7
Hz), 6.97 (1H, d, J=8.5 Hz), 4.55-4.54 (2H, m), 4.30-4.29 (2H, m),
4.05-4.04 (3H, m), 3.05-2.98 (1H, m), 1.44 (6H, d, J=6.7 Hz).
MS spectrum (ES/APCI.sup.+): 450 (M+H), 452 (M+2+H)
(Example 6)
5-chloro-N-(5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2--
methoxybenzenesulfonamide
##STR00023##
(6a) 5-bromo-2-chloro-3-(1H-imidazol-2-yl)pyridine
To a solution of 5-bromo-2-chloro-pyridine-3-carbaldehyde (2.00 g,
9.07 mmol) in isopropanol (20 mL) and water (20 mL), ammonium
acetate (6.29 g, 81.7 mmol) and an aqueous solution of glyoxal (39%
content, 3.09 mL, 27.2 mmol) at room temperature and the mixture
was stirred at the same temperature as above for 3 days. The
mixture was concentrated under reduce pressure, and the residue was
diluted by addition of water, followed by extraction with ethyl
acetate. The organic layer was washed with a saturated aqueous
solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (n-hexane/ethyl acetate=100/0-0/100) to
obtain the title compound (1.25 g, yield: 53%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.86-8.78 (2H,
m), 8.42-8.40 (2H, m).
(6b)
5-bromo-3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-imidazol-2--
yl]-2-chloropyridine
To a solution of 5-bromo-2-chloro-3-(1H-imidazol-2-yl)pyridine (830
mg, 3.21 mmol) obtained in Example (6a) and
(2-Bromoethoxy)-tert-butyldimethylsilane (1.92 g, 8.03 mmol) in
N,N-dimethylformamide (30 mL), potassium carbonate (2.22 g, 16.1
mmol) at room temperature, the mixture was stirred at the same
temperature as above for 24 hours, and subsequently stirred at
60.degree. C. for 5 hours in an oil bath. The mixture was cooled to
room temperature, and diluted by addition of water, followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-40/60) to obtain the title compound (948 mg, yield:
71%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.55 (1H, d,
J=2.7 Hz), 8.01 (1H, d, J=2.7 Hz), 7.20 (1H, d, J=1.2 Hz), 7.18
(1H, d, J=1.2 Hz), 3.95 (2H, t, J=5.1 Hz), 3.78 (2H, t, J=5.3 Hz),
0.83 (9H, s), -0.03 (6H, s).
(6c)
10-bromo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine
To a solution of
5-bromo-3-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-imidazol-2-yl]--
2-chloropyridine (948 mg, 2.27 mmol) obtained in Example (6b) in
tetrahydrofuran (20 mL), a 1.0 mol/L solution of tetrabutyl
ammonium fluoride in tetrahydrofuran (4.5 mL, 4.5 mmol) was added
at room temperature, the mixture was stirred at the same
temperature as above for 3 days, and subsequently stirred at
60.degree. C. for 8 hours in an oil bath. The mixture was cooled in
an ice water bath, diluted by addition of a saturated aqueous
solution of ammonium chloride, followed by extraction with ethyl
acetate. The organic layer was washed with a saturated aqueous
solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (ethyl acetate/methanol=100/0-90/10) to
obtain the title compound (364 mg, yield: 60%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.03-9.01 (1H,
m), 8.26-8.24 (1H, m), 7.20-7.19 (1H, m), 7.04 (1H, s), 4.60-4.58
(2H, m), 4.46-4.44 (2H, m).
(6d) tert-butyl
5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
To a solution of
10-bromo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine (65.0
mg, 0.24 mmol) obtained in Example (6c) in 1,4-dioxane (5 mL),
tert-butyl carbamate (34.3 mg, 0.29 mmol), palladium (II) acetate
(6.0 mg, 0.027 mmol),
dicyclohexyl[3,6-dimethoxy-2',4',6'-tris(1-methylethyl)[1,1'-biphe-
nyl]-2-yl]phosphine (39.3 mg, 0.073 mmol) and cesium carbonate (111
mg, 0.34 mmol) was added at room temperature, and the mixture was
stirred under nitrogen atmosphere at 100.degree. C. for 10 hours in
an oil bath. The mixture was cooled to room temperature, and
diluted by addition of water, followed by extraction with ethyl
acetate. The organic layer was washed with a saturated aqueous
solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (ethyl acetate/methanol=100/0-85/15) to
obtain the title compound (42 mg, yield: 57%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.77 (1H, d,
J=2.7 Hz), 8.40 (1H, br s), 7.16 (1H, d, J=1.2 Hz), 7.01-6.92 (2H,
m), 4.56-4.54 (2H, m), 4.44-4.42 (2H, m), 1.52 (9H, s).
(6e)
5-chloro-N-(5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
)-2-methoxybenzenesulfonamide
To a solution of tert-butyl
5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
(42.0 mg, 0.14 mmol) obtained in Example (6d) in methanol (3 mL), a
4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (3 mL, 12
mmol) was added at room temperature, the mixture was stirred at
room temperature for 2 hours. The mixture was concentrated under
reduce pressure, and the residue was diluted by addition of a
saturated aqueous solution of sodium bicarbonate. The solvent was
distilled off under reduced pressure to obtain
5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-10-amine as a
mixture containing inorganic materials. To a mixture of
5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-10-amine as a
mixture containing inorganic materials in pyridine (0.224 mL, 2.78
mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (40.2 mg, 0.17
mmol) was added, and the mixture was stirred at 80.degree. C. for
3.5 hours in an oil bath. After cooling, the mixture was
concentrated under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (ethyl
acetate/methanol=100/0-90/10) to obtain the solid. The solid was
dissolved into tetrahydrofuran (5 mL), a 1.0 mol/L solution of
tetrabutyl ammonium fluoride in tetrahydrofuran (4.5 mL, 4.5 mmol)
was added thereto at room temperature, and the mixture was stirred
at room temperature for 1 hour. The mixture was diluted by addition
of a saturated aqueous solution of ammonium chloride, and followed
by extraction with ethyl acetate.
The organic layer was washed with a saturated aqueous solution of
sodium chloride and dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (ethyl acetate/methanol=100/0-85/15) to obtain the title
compound (29 mg, yield for 3 steps: 51%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.28 (1H, br s),
8.57 (1H, d, J=2.7 Hz), 7.90 (1H, d, J=2.7 Hz), 7.67-7.64 (2H, m),
7.35 (1H, br s), 7.25 (1H, d, J=9.8 Hz), 7.07 (1H, br s), 4.48-4.46
(2H, m), 4.42-4.40 (2H, m), 3.91 (3H, s).
MS spectrum (ES/APCI.sup.+): 407 (M+H), 409 (M+2+H)
(Example 7)
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-
-methoxybenzenesulfonamide
##STR00024##
(7a)
10-bromo-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepine
A mixture of 1-(5-bromo-2-chloropyridin-3-yl)ethanone (4.85 g, 0.85
mmol) and N,N-dimethylformamide dimethyl acetal (15 mL, 113 mmol)
was stirred at 85.degree. C. for 90 minutes in an oil bath. The
mixture was cooled to room temperature, and concentrated under
reduce pressure. The residue was diluted by addition of ethanol (30
mL) and water (15 mL), acetic acid (3.3 mL, 58 mmol) and
2-hydrazinoethanol (1.83 mL, 26.9 mmol) was added thereto at room
temperature, and the mixture was stirred at 90.degree. C. for 4
hours in an oil bath. The mixture was cooled to room temperature,
and neutralized by addition of a 1.0 mol/L aqueous solution of
sodium hydroxide, followed by extraction with chloroform. The
organic layer was washed with a saturated aqueous solution of
sodium chloride and dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (n-hexane/ethyl acetate=100/0-0/100) to obtain
2-[5-(5-bromo-2-chloropyridin-3-yl)-1H-pyrazol-1-yl]ethanol (3.62
g) as a mixture containing positional isomers. To a solution of
2-[5-(5-bromo-2-chloropyridin-3-yl)-1H-pyrazol-1-yl]ethanol (3.62
g) as a mixture containing positional isomers obtained in the above
step in N,N-dimethylformamide (240 mL) was added potassium
carbonate (3.31 g, 23.9 mmol) at room temperature, and the mixture
was stirred at 120.degree. C. for 2 hours in an oil bath. The
reaction mixture was cooled, and an insoluble material was filtered
off. The residue was washed with ethyl acetate, and the filtrate
and the washes were combined. The solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (Yamazen Co. Ltd., High-Flash.TM. column
Amino, n-hexane/ethyl acetate=100/0-30/70) to obtain the title
compound (101 mg, yield for 2 steps: 57%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.27 (1H, d,
J=2.3 Hz), 8.18 (1H, d, J=2.3 Hz), 7.55 (1H, d, J=2.0 Hz), 6.69
(1H, d, J=2.0 Hz), 4.74-4.72 (2H, m), 4.62-4.60 (2H, m).
(7b) tert-butyl
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
To a mixture of
10-bromo-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepine
(3.15 g, 11.8 mmol) obtained in Example (7a) in toluene (130 mL),
tert-butyl carbamate (1.66 g, 14.2 mmol),
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (613.5
mg, 0.59 mmol),
2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.01 g,
2.37 mmol) and sodium tert-butoxide (2.64 g, 27.5 mmol) was added
at room temperature, and the mixture was stirred under nitrogen
atmosphere at the same temperature as above for 15 hours. The
mixture was diluted by addition of water, and an insoluble material
was filtered off through pad of Celite 545.RTM.. The residue was
washed with ethyl acetate, and the filtrate and the washes were
combined. The organic layer was separated, washed with a saturated
aqueous solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (n-hexane/ethyl acetate=100/0-20/80) to
obtain the title compound (2.07 g, yield: 58%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.44 (1H, br
s), 8.07 (1H, br d, J=2.7 Hz), 7.53 (1H, br d, J=2.7 Hz), 6.74-6.65
(2H, m), 4.72-4.71 (2H, m), 4.58-4.57 (2H, m), 1.54 (9H, s).
(7c)
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-y-
l)-2-methoxybenzenesulfonamide
To a solution of tert-butyl
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
(53.0 mg, 0.18 mmol) obtained in Example (7b) in methanol (10 mL),
a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (5 mL, 20
mmol) was added at room temperature, the mixture was stirred at the
same temperature as above for 1 hour. The mixture was concentrated
under reduce pressure. The residue was diluted with pyridine (0.282
mL, 3.51 mmol), 5-chloro-2-methoxybenzenesulfonyl chloride (46.5
mg, 0.19 mmol) was added thereto at room temperature, and the
mixture was stirred at 80.degree. C. for 2 hours in an oil bath.
After cooling, the mixture was concentrated under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (ethyl acetate/methanol=100/0-90/10) to obtain the title
compound (36 mg, yield: 51%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.28 (1H, br s),
7.93 (1H, d, J=2.3 Hz), 7.87 (1H, d, J=2.3 Hz), 7.69-7.67 (2H, m),
7.54 (1H, d, J=2.0 Hz), 7.26 (1H, d, J=9.0 Hz), 6.67 (1H, d, J=2.0
Hz), 4.61-4.60 (2H, m), 4.49-4.48 (2H, m), 3.89 (3H, s).
MS spectrum (ES/APCI.sup.+): 407 (M+H), 409 (M+2+H)
(Example 8) Potassium [(5-chloro-2-methoxyphenyl)
sulfonyl](5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)azan-
ide (Potassium Salt of Example 7)
##STR00025##
To a suspension of
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-
-methoxybenzenesulfonamide (28 mg, 0.069 mmol) obtained in Example
(7c) in ethanol (5 mL), a solution of 0.5 N potassium hydroxide in
ethanol (0.137 mL, 0.069 mmol) was added at room temperature, and
the mixture was stirred at the same temperature as above for 1
hour. The solvent was distillated off under reduce pressure to
obtain the title compound (31 mg, yield: quantitative).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.73 (1H, d, J=2.7
Hz), 7.62 (1H, d, J=2.7 Hz), 7.55 (1H, d, J=2.3 Hz), 7.47 (1H, d,
J=2.0 Hz), 7.34 (1H, dd, J=8.6, 2.3 Hz), 6.99 (1H, d, J=8.6 Hz),
6.52 (1H, d, J=2.0 Hz), 4.53-4.52 (2H, m), 4.36-4.35 (3H, m), 3.65
(3H, s).
(Example 9)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluorobenzenesulfonamide
##STR00026##
(9a) 5-Fluoro-2-ethoxybenzenesulfonyl chloride
To chlorosulfonic acid (30.0 mL, 451 mmol),
1-ethoxy-4-fluorobenzene (10.33 mL, 73.7 mmol) was added at
-12.degree. C. over 10 minutes, the mixture was stirred at the same
temperature as above for 30 minutes, and subsequently stirred in an
ice water bath for 1 hour. The reaction mixture was carefully
poured into ice (approximately 300 mL), followed by extraction with
ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium chloride and dried over anhydrous
magnesium sulfate. After filtration, the solvent was distilled off
under reduced pressure, and the residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate=4/1). To the obtained
solid, n-hexane was added, and the suspension was cooled in ice
water bath. The precipitated solid was collected by filtration,
washed with n-hexane, and then dried to obtain the title compound
(7.69 g, yield: 44%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.70 (1H, dd,
J=7.4, 3.1 Hz), 7.41-7.36 (1H, m), 7.07 (1H, dd, J=9.4, 3.9 Hz),
4.26 (2H, q, J=6.8 Hz), 1.55 (3H, t, J=6.8 Hz).
(9b)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-etho-
xy-5-fluorobenzenesulfonamide
To a solution of tert-butyl
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
(48.0 mg, 0.16 mmol) obtained in Example (7b) in methanol (10 mL),
a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (5 mL, 20
mmol) was added at room temperature, the mixture was stirred at the
same temperature as above for 1 hour. The mixture was concentrated
under reduce pressure. The residue was diluted with pyridine (0.256
mL, 3.18 mmol), 5-Fluoro-2-ethoxybenzenesulfonyl chloride (42.0 mg,
0.18 mmol) obtained in Example (9a) was added thereto at room
temperature, and the mixture was stirred at 80.degree. C. for 30
minutes in an oil bath. After cooling, the mixture was concentrated
under reduced pressure, and the residue was purified in an
automatic chromatography apparatus (ethyl
acetate/methanol=100/0-95/5) to obtain the title compound (49 mg,
yield: 76%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.13 (1H, br s),
7.92 (1H, d, J=2.3 Hz), 7.88 (1H, d, J=2.3 Hz), 7.58 (1H, dd,
J=8.2, 3.1 Hz), 7.54 (1H, d, J=2.0 Hz), 7.49-7.44 (1H, m),
7.26-7.23 (1H, m), 6.64 (1H, d, J=2.0 Hz), 4.60 (2H, t, J=3.9 Hz),
4.48 (2H, t, J=3.9 Hz), 4.17 (2H, q, J=7.0 Hz), 1.27 (3H, t, J=7.0
Hz).
MS spectrum (ES/APCI.sup.+): 405 (M+H)
(Example 10) Potassium
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl[(2-ethoxy-5-fl-
uorophenyl)sulfonyl]azanide (Potassium Salt of Example 9)
##STR00027##
To a suspension of
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluorobenzenesulfonamide (37.0 mg, 0.092 mmol) obtained in Example
(9b) in ethanol (3 mL), a solution of 0.5 N potassium hydroxide in
ethanol (0.182 mL, 0.092 mmol) was added at room temperature, and
the mixture was stirred at the same temperature as above for 1
hour. The solvent was distillated off under reduce pressure to
obtain the title compound (44 mg, yield: quantitative) H NMR
spectrum (DMSO-d6, 400 MHz) .delta.: .delta.: 7.65 (1H, d, J=2.7
Hz), 7.59 (1H, d, J=2.7 Hz), 7.50-7.47 (2H, m), 7.11-7.08 (1H, m),
6.96 (1H, dd, J=9.0, 4.3 Hz), 6.51 (1H, d, J=2.0 Hz), 4.53-4.52
(2H, m), 4.37-4.34 (2H, m), 3.91 (2H, q, J=7.0 Hz), 1.10 (3H, t,
J=7.0 Hz).
(Example 11)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-5-fluoro-2-
-(2-methoxyethoxy)benzenesulfonamide
##STR00028##
(11a) 2-bromo-4-fluoro-1-(2-methoxyethoxy)benzene
To a solution of 2-Bromo-4-fluorophenol (3.39 g, 17.7 mmol) and
2-Bromoethyl Methyl Ether (2.55 mL, 26.8 mmol) in
N,N-dimethylformamide (35 mL), potassium carbonate (4.92 g, 35.6
mmol) was added at room temperature, the mixture was stirred at the
same temperature as above for 2 hours, and subsequently stirred at
60.degree. C. for 2 hours. The mixture was cooled to room
temperature, and diluted by addition of water, followed by
extraction with ethyl acetate. The organic layer was washed with
water twice and a saturated aqueous solution of sodium chloride,
and dried over anhydrous magnesium sulfate. After filtration, the
solvent was distilled off under reduced pressure, and the residue
was purified by silica gel column chromatography (n-hexane/ethyl
acetate=4/1) to obtain the title compound (4.34 g, yield: 98%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.29 (1H, dd,
J=7.8, 2.7 Hz), 6.99-6.96 (1H, m), 6.89 (1H, dd, J=9.0, 4.7 Hz),
4.15-4.13 (2H, m), 3.80-3.79 (2H, m), 3.48 (3H, s).
(11b) 5-fluoro-2-(2-methoxyethoxy)benzenesulfonyl chloride
To a mixture of 2-bromo-4-fluoro-1-(2-methoxyethoxy)benzene (3.42
g, 13.7 mmol) obtained in Example (11a), phenylmethanethiol (1.62
mL, 13.8 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.3150 g,
0.34 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (0.3930
g, 0.68 mmol) in 1,4-dioxane (70 mL), N,N-Diisopropylethylamine
(4.8 mL, 28 mmol) was added at room temperature, the mixture was
stirred under nitrogen atmosphere at 100.degree. C. for 8 hours in
an oil bath. The mixture was cooled, and concentrated under reduced
pressure. The residue was diluted by addition of water, followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium bicarbonate and a saturated
aqueous solution of sodium chloride, and dried over anhydrous
magnesium sulfate. After filtration, the solvent was distilled off
under reduced pressure, and the residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate=6/1) to obtain
2-(benzylsulfanyl)-4-fluoro-1-(2-methoxyethoxy)benzene (5.02 g) as
a mixture containing unknown materials. To a mixture of
2-(benzylsulfanyl)-4-fluoro-1-(2-methoxyethoxy)benzene (5.02 g)
obtained the above step, acetic acid (7.8 mL, 140 mmol) and water
(3.5 mL) in acetonitrile (70 mL),
1,3-dichloro-5,5-dimethylhydantoin (5.41 g, 27.5 mmol) was added
under ice cooling over 5 minutes in several portions, and the
mixture was stirred at the same temperature as above for 20
minutes. The mixture was concentrated under reduced pressure,
diluted by addition of a saturated aqueous solution of sodium
bicarbonate, extracted with ethyl acetate. The organic layer was
washed with water and a saturated aqueous solution of sodium
chloride and dried over anhydrous magnesium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified by column chromatography
(n-hexane/ethyl acetate=4/1-2/1) to obtain the title compound (3.66
g, yield for 2 steps: 99%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.69 (1H, dd,
J=7.4, 3.1 Hz), 7.40-7.37 (1H, m), 7.16 (1H, dd, J=9.2, 4.1 Hz),
4.34-4.32 (2H, m), 3.87-3.85 (2H, m), 3.47 (3H, s).
(11c)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-5-flu-
oro-2-(2-methoxyethoxy)benzenesulfonamide
The title compound (46 mg, yield: 46%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
(70.0 mg, 0.23 mmol) obtained in Example (7b) and
5-fluoro-2-(2-methoxyethoxy)benzenesulfonyl chloride (77.3 mg, 0.29
mmol) obtained in Example (11b) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 9.83 (1H, br s),
7.95 (1H, d, J=2.3 Hz), 7.91 (1H, d, J=2.3 Hz), 7.56-7.46 (3H, m),
7.33 (1H, dd, J=9.2, 4.1 Hz), 6.70 (1H, d, J=2.0 Hz), 4.61-4.60
(2H, m), 4.49-4.48 (2H, m), 4.31 (2H, t, J=4.7 Hz), 3.73 (2H, t,
J=4.7 Hz), 3.29 (3H, s).
MS spectrum (ES/APCI.sup.+): 435 (M+H).
(Example 12)
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-
-methoxypyridine-3-sulfonamide
##STR00029##
(12a) 5-chloro-2-methoxypyridine-3-sulfonyl chloride
To a mixture of 3-bromo-5-chloro-2-methoxypyridine (2.24 g, 10.1
mmol), phenylmethanethiol (1.18 mL, 10.1 mmol),
Tris(dibenzylideneacetone)dipalladium(0) (0.2319 g, 0.25 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (0.2955
g, 0.51 mmol) in 1,4-dioxane (100 mL), N,N-Diisopropylethylamine
(3.5 mL, 20 mmol) was added at room temperature, the mixture was
stirred under nitrogen atmosphere at 100.degree. C. for 30 minutes
in an oil bath. The mixture was cooled, and concentrated under
reduced pressure. The residue was diluted by addition of water,
followed by extraction with ethyl acetate. The organic layer was
washed with a saturated aqueous solution of sodium bicarbonate and
a saturated aqueous solution of sodium chloride, and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
by silica gel column chromatography (n-hexane/ethyl acetate=15/1)
to obtain 3-(benzylsulfanyl)-5-chloro-2-methoxypyridine (2.76 g) as
a mixture containing unknown materials. To a mixture of
3-(benzylsulfanyl)-5-chloro-2-methoxypyridine (2.76 g) obtained the
above step, acetic acid (5.8 mL, 100 mmol) and water (2.5 mL, 139
mmol) in acetonitrile (50 mL), 1,3-dichloro-5,5-dimethylhydantoin
(3.97 g, 20.2 mmol) was added under ice cooling over 5 minutes in
several portions, and the mixture was stirred at the same
temperature as above for 20 minutes. The mixture was concentrated
under reduced pressure, and diluted by addition of a saturated
aqueous solution of sodium bicarbonate, followed by extraction with
ethyl acetate. The organic layer was washed with water and a
saturated aqueous solution of sodium chloride and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
by column chromatography (n-hexane/ethyl acetate=4/1-2/1). To the
obtained solid, n-hexane (4 mL) was added, the precipitated solid
was collected by filtration, washed with n-hexane, and then dried
to obtain the title compound (1.86 g, yield for 2 steps: 76%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.43 (1H, d,
J=2.7 Hz), 8.22 (1H, d, J=2.7 Hz), 4.19 (3H, s).
(12b)
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10--
yl)-2-methoxypyridine-3-sulfonamide
The title compound (47 mg, yield: 57%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
(61.0 mg, 0.20 mmol) obtained in Example (7b) and
5-chloro-2-methoxypyridine-3-sulfonyl chloride (54.2 mg, 0.22 mmol)
obtained in Example (12a) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.55 (1H, br s),
8.49 (1H, d, J=2.3 Hz), 8.20 (1H, d, J=2.3 Hz), 7.96 (1H, d, J=2.3
Hz), 7.89 (1H, d, J=2.3 Hz), 7.54 (1H, d, J=2.0 Hz), 6.72 (1H, d,
J=2.0 Hz), 4.63-4.61 (2H, m), 4.51-4.50 (2H, m), 3.96 (3H, s).
MS spectrum (ES/APCI.sup.+): 408 (M+H), 410 (M+2+H)
(Example 13)
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-
-ethoxypyridine-3-sulfonamide
##STR00030##
(13a) 3-bromo-5-chloro-2-ethoxypyridine
To a solution of 4-bromo-5-chloro-2-fluoro-pyridine (2.00 g, 9.50
mmol) in ethanol (50 mL), a 20% ethanol solution of sodium ethoxide
(6.12 mL, 14.3 mmol) was added at room temperature, and the mixture
was stirred at 80.degree. C. for 1 hour in an oil bath. The mixture
was cooled, and concentrated under reduced pressure. The residue
was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=100/0-90/10) to obtain the title compound
(2.155 g, yield: 96%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.02 (1H, d,
J=2.7 Hz), 7.48 (1H, d, J=2.7 Hz), 4.07 (2H, q, J=7.0 Hz), 1.44
(3H, t, J=7.0 Hz).
(13b) 5-chloro-2-ethoxypyridine-3-sulfonyl chloride
The title compound (1.39 g, yield for 2 steps: quantitative) was
obtained by production according to the method described in
Examples (12a) using 3-bromo-5-chloro-2-ethoxypyridine (1.04 g,
4.40 mmol) obtained in Example (13a) as a starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.40 (1H, d,
J=2.3 Hz), 8.20 (1H, d, J=2.3 Hz), 4.63 (2H, q, J=7.0 Hz), 1.50
(3H, t, J=7.0 Hz).
(13c)
5-chloro-N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10--
yl)-2-ethoxypyridine-3-sulfonamide
The title compound (91 mg, yield: 93%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
(70.0 mg, 0.23 mmol) obtained in Example (7b) and
5-chloro-2-ethoxypyridine-3-sulfonyl chloride (96.0 mg, 0.37 mmol)
obtained in Example (13b) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.49 (1H, br s),
8.47 (1H, d, J=2.7 Hz), 8.22 (1H, d, J=2.7 Hz), 7.96 (1H, d, J=2.7
Hz), 7.92 (1H, d, J=2.7 Hz), 7.54 (1H, d, J=2.0 Hz), 6.69 (1H, d,
J=2.0 Hz), 4.62-4.61 (2H, m), 4.50-4.49 (2H, m), 4.44 (2H, q, J=7.0
Hz), 1.25 (3H, t, J=7.0 Hz).
MS spectrum (ES/APCI.sup.+): 422 (M+H), 424 (M+2+H)
(Example 14)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluoropyridine-3-sulfonamide
##STR00031##
(14a) 3-bromo-2-ethoxy-5-fluoropyridine
To a mixture of 3-bromo-5-fluoro-pyridin-2-amine (1.50 g, 7.85
mmol) and hydrogen fluoride pyridine (4 mL, 44 mmol), sodium
nitrite was added at -10.degree. C. in a several portions, and the
mixture was stirred at room temperature for 2 hours. The mixture
was diluted by addition of a saturated aqueous solution of sodium
bicarbonate until it became basic, followed by extraction with
ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium chloride, and dried over anhydrous
magnesium sulfate. After filtration, the solvent was distilled off
under reduced pressure to obtain a crude product of
3-bromo-2,5-difluoro-pyridine (1.00 g). To a solution of a crude
product of 3-bromo-2,5-difluoro-pyridine (1.00 g) obtained in the
above step in ethanol (20 mL), a 20% ethanol solution of sodium
ethoxide (2.84 mL, 6.61 mmol) was added at room temperature, and
the mixture was stirred at 80.degree. C. for 1 hour in an oil bath.
The mixture was cooled, and concentrated under reduced pressure.
The residue was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=100/0-90/10) to obtain the title compound
(1.04 g, yield for 2 steps: 66%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.02 (1H, d,
J=2.3 Hz), 7.80 (1H, d, J=2.3 Hz), 4.41 (2H, q, J=7.0 Hz), 1.43
(3H, t, J=7.0 Hz).
(14b) 2-ethoxy-5-fluoropyridine-3-sulfonyl chloride
3-(benzylsulfanyl)-2-ethoxy-5-fluoropyridine
To a mixture of 3-bromo-2-ethoxy-5-fluoropyridine (2.60 g, 11.8
mmol) obtained in Example (14a), phenylmethanethiol (1.39 mL, 11.8
mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.2702 g, 0.30
mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)
(0.3415 g, 0.59 mmol) in 1,4-dioxane (120 mL),
N,N-Diisopropylethylamine (4.11 mL, 23.6 mmol) was added at room
temperature, the mixture was stirred under nitrogen atmosphere at
100.degree. C. for 4 hours in an oil bath. The mixture was cooled,
and concentrated under reduced pressure. The residue was diluted by
addition of water, followed by extraction with ethyl acetate. The
organic layer was washed with a saturated aqueous solution of
sodium chloride, and dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (n-hexane/ethyl acetate=100/0-90/10) to obtain
3-(benzylsulfanyl)-2-ethoxy-5-fluoropyridine (3.11 g) as a mixture
containing unknown materials. To a mixture of
3-(benzylsulfanyl)-2-ethoxy-5-fluoropyridine (3.11 g) obtained the
above step, acetic acid (0.9 mL, 16 mmol) and water (0.6 mL, 33
mmol) in acetonitrile (60 mL), 1,3-dichloro-5,5-dimethylhydantoin
(4.65 g, 23.6 mmol) was added under ice cooling in several
portions, and the mixture was stirred at the same temperature as
above for 3 hours. The mixture was allowed to warm up to room
temperature, concentrated under reduced pressure, and the residue
was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=100/0-80/20) to obtain the title compound
(2.67 g, yield for 2 steps: 94%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.34 (1H, d,
J=3.1 Hz), 8.02 (1H, dd, J=6.6, 3.1 Hz), 4.61 (2H, q, J=7.0 Hz),
1.49 (3H, t, J=7.0 Hz).
(14c)
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-eth-
oxy-5-fluoropyridine-3-sulfonamide
To a solution of tert-butyl
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-ylcarbamate
(70.0 mg, 0.23 mmol) obtained in Example (7b) in methanol (10 mL),
a 4.0 mol/L solution of hydrogen chloride in 1,4-dioxane (5 mL, 20
mmol) was added at room temperature, the mixture was stirred at the
same temperature as above for 4 hours. The mixture was concentrated
under reduce pressure. The residue was diluted with pyridine (0.373
mL, 4.63 mmol), 2-ethoxy-5-fluoropyridine-3-sulfonyl chloride (83.2
mg, 0.35 mmol) obtained in Example (14b) was added thereto at room
temperature, and the mixture was stirred at 80.degree. C. for 2
hours in an oil bath. After cooling, the mixture was concentrated
under reduced pressure, and the residue was purified in an
automatic chromatography apparatus (ethyl
acetate/methanol=100/0-90/10) to obtain the title compound (86 mg,
yield: 92%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.49 (1H, br s),
8.43 (1H, d, J=3.1 Hz), 8.17 (1H, dd, J=7.4, 3.1 Hz), 7.96 (1H, d,
J=2.7 Hz), 7.92 (1H, d, J=2.7 Hz), 7.54 (1H, d, J=2.3 Hz), 6.69
(1H, d, J=2.3 Hz), 4.62-4.60 (2H, m), 4.50-4.48 (2H, m), 4.43 (2H,
q, J=7.0 Hz), 1.25 (3H, t, J=7.0 Hz).
MS spectrum (ES/APCI.sup.+): 406 (M+H)
(Example 15) Potassium
5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl[(2-ethoxy-5-fl-
uoropyridin-3-yl)sulfonyl]azanide (Potassium Salt of Example
14)
##STR00032##
To a suspension of
N-(5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl)-2-ethoxy-5-
-fluoropyridine-3-sulfonamide (66.0 mg, 0.16 mmol) obtained in
Example (14c) in ethanol (5 mL), a solution of 0.5 N potassium
hydroxide in ethanol (0.325 mL, 0.16 mmol) was added at room
temperature, and the mixture was stirred at room temperature for 1
hour. The solvent was distillated off under reduce pressure to
obtain the title compound (80 mg, yield: quantitative).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 8.07 (1H, d, J=3.1
Hz), 7.87 (1H, dd, J=8.2, 3.1 Hz), 7.71 (1H, d, J=2.7 Hz), 7.64
(1H, d, J=2.7 Hz), 7.48 (1H, d, J=2.0 Hz), 6.57 (1H, d, J=2.0 Hz),
4.55-4.52 (2H, m), 4.38-4.35 (3H, m), 4.18 (2H, q, J=7.0 Hz), 1.05
(3H, t, J=7.0 Hz).
(Example 16)
5-chloro-2-methoxy-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2--
f][1,4]oxazepin-10-yl]benzenesulfonamide
##STR00033##
(16a) methyl (2S)-2-hydrazinylpropanoate hydrochloride
To a solution of methyl (2R)-2-hydroxypropanoate (4.14 g, 39.8
mmol) and 2.6-lutidine (10.5 mL, 85.8 mmol) in methylene chloride
(55 mL), was added trifluoromethanesulfonic acid anhydride (7.4 mL,
44.1 mmol) under ice cooling, and the mixture was stirred at the
same temperature as above for 15 minutes. To the mixture, a
solution of tert-butyl carbazate (5.33 g, 40.3 mmol) under ice
cooling over 25 minutes, and the mixture was stirred at the same
temperature as above for 4 hours. The mixture was allowed to warm
up to room temperature, and the solvent was distillated off under
reduce pressure. The residue was diluted by addition of ether (70
mL), and the mixture was stored at -20.degree. C. for 3 days. The
mixture was allowed to warm up to room temperature, and the
precipitated solid was filtered off through pad of celite 545.RTM..
The filtrate was washed with water and a saturated aqueous solution
of sodium chloride and dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (n-hexane/ethyl acetate=65/35-40/60) to obtain tert-butyl
2-[(2S)-1-methoxy-1-oxopropan-2-yl]hydrazinecarboxylate (5.96 g) as
a mixture containing some unknown materials. To a solution of
tert-butyl 2-[(2S)-1-methoxy-1-oxopropan-2-yl]hydrazinecarboxylate
(5.96 g) obtained in the above step in methanol (100 mL), a 1.0
mol/L aqueous solution of sodium hydroxide (55 mL, 55 mmol) was
added at room temperature, and the mixture was stirred at room
temperature for 2 days. Most of the organic solvent was distillated
off under reduce pressure, ether was added thereto, the aqueous
layer was separated. The aqueous layer was acidified by addition of
2.0 mol/L hydrochloric acid, followed by extraction with a mixed
solvent of chloroform/isopropanol=4/1. The organic layer was dried
over anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure to obtain a crude product of
(2S)-2-[2-(tert-butoxycarbonyl)hydrazinyl]propanoic acid (3.45 g).
To a solution of the crude product of
(2S)-2-[2-(tert-butoxycarbonyl)hydrazinyl]propanoic acid (3.45 g)
obtained in the above step in methanol (35 mL), thionyl chloride
(2.44 mL, 33.6 mmol) was added under ice cooling, and the mixture
was stirred at room temperature for 14 hours. The solvent was
distillated off under reduce pressure to obtain the title compound
(2.55 g, yield for 3 steps: 42%)
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 3.82 (1H, q, J=7.3
Hz), 3.70 (3H, s), 1.26 (3H, d, J=7.3 Hz).
(16b)
(5S)-10-bromo-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]o-
xazepine
A mixture of 1-(5-bromo-2-chloropyridin-3-yl)ethanone (980 mg, 3.97
mmol) and N,N-dimethylformamide dimethyl acetal (4.0 mL, 30 mmol)
was stirred at 90.degree. C. for 90 minutes in an oil bath. The
mixture was cooled to room temperature, and concentrated under
reduce pressure. The residue was diluted by addition of ethanol (13
mL) and water (6.5 mL), acetic acid (1.6 mL, 28 mmol) and methyl
(2S)-2-hydrazinylpropanoate hydrochloride (0.859 g, 5.56 mmol)
obtained in Example (16a) was added thereto at room temperature,
and the mixture was stirred at 90.degree. C. for 4 hours in an oil
bath. The mixture was cooled to room temperature, and neutralized
by addition of a 2.0 mol/L aqueous solution of sodium hydroxide,
followed by extraction with chloroform. The organic layer was
washed with a saturated aqueous solution of sodium chloride and
dried over anhydrous sodium sulfate. After filtration, the solvent
was distilled off under reduced pressure to obtain a crude product
of
(2S)-2-[5-(5-bromo-2-chloropyridin-3-yl)-1H-pyrazol-1-yl]propanoic
acid (1.39 g) as a mixture containing a positional isomer. To a
solution of the crude product of
(2S)-2-[5-(5-bromo-2-chloropyridin-3-yl)-1H-pyrazol-1-yl]propanoic
acid (1.31 g) obtained in the above step in tetrahydrofuran (10
mL), a 0.92 mol/L solution of boran-tetrahydrofuran complex in
tetrahydrofuran (6.5 mL, 6.0 mmol) was added under ice cooling, the
mixture was stirred at the same temperature as above for 10 minutes
and subsequently stirred at room temperature for 20 hours. The
mixture was cooled in an ice water bath, a 1.0 mol/L aqueous
solution of sodium hydroxide was added thereto, followed by
extraction with a mixed solvent of ethyl acetate/n-hexane=4/1. The
organic layer was washed with water and a saturated aqueous
solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure to obtain a crude product of
(2S)-2-[5-(5-bromo-2-chloropyridin-3-yl)-1H-pyrazol-1-yl]propan-1-ol
(760 mg) as a mixture containing a positional isomer. To a solution
of the crude product of
(2S)-2-[5-(5-bromo-2-chloropyridin-3-yl)-1H-pyrazol-1-yl]propan-1-ol
(760 mg) as a mixture containing positional isomers obtained in the
above step in N,N-dimethylformamide (50 mL) was added potassium
carbonate (829 mg, 6.00 mmol) at room temperature, and the mixture
was stirred at 120.degree. C. for 2 hours in an oil bath. The
reaction mixture was cooled, and diluted by addition of a saturated
aqueous solution of ammonium chloride, followed by extraction with
a mixed solvent of ethyl acetate/n-hexane=4/1. The organic layer
was washed with a saturated aqueous solution of ammonium chloride
and a saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, the residue was purified in
an automatic chromatography apparatus (Yamazen Co. Ltd.,
High-Flash.TM. column Amino, n-hexane/ethyl acetate=96/4-66/34) to
obtain the title compound (597 mg, yield for 3 steps: 54%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.26 (1H, d,
J=2.4 Hz), 8.19 (1H, d, J=2.4 Hz), 7.55 (1H, d, J=1.8 Hz), 6.66
(1H, d, J=1.8 Hz), 4.95-4.89 (1H, m), 4.59 (1H, dd, J=13.1, 4.6
Hz), 4.44-4.43 (1H, m), 1.64 (3H, d, J=7.3 Hz).
(16c) tert-butyl
[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate
To a mixture of
(5S)-10-bromo-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazep-
ine (590 mg, 2.11 mmol) obtained in Example (16b) in toluene (10
mL), tert-butyl carbamate (321 mg, 2.74 mmol),
Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (109 mg,
0.11 mmol), 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl
(179 mg, 0.42 mmol) and sodium tert-butoxide (466 mg, 4.84 mmol)
were added at room temperature, and the mixture was stirred under
nitrogen atmosphere at the same temperature as above for 17 hours.
The mixture was diluted by addition of ethyl acetate and a
saturated aqueous solution of ammonium chloride, followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (n-hexane/ethyl
acetate=61/39-40/60). To the obtained solid, diisopropyl ether was
added, the precipitated solid was collected by filtration, washed
with diisopropyl ether, and then dried to obtain the title compound
(493 mg, yield: 74%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.43 (1H, br
s), 8.06 (1H, d, J=2.4 Hz), 7.54 (1H, d, J=1.8 Hz), 6.71 (1H, d,
J=1.8 Hz), 6.55 (1H, br s), 4.91-4.88 (1H, m), 4.55 (1H, dd,
J=12.8, 4.3 Hz), 4.41 (1H, dd, J=12.8, 1.2 Hz), 1.64 (3H, d, J=6.7
Hz), 1.54 (9H, s).
(16d)
5-chloro-2-methoxy-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido-
[3,2-f][1,4]oxazepin-10-yl]benzenesulfonamide
The title compound (108 mg, yield: 90%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate (90.1 mg, 0.29 mmol) obtained in Example (16c) and
5-chloro-2-methoxybenzenesulfonyl chloride (72.8 mg, 0.30 mmol) as
starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.29 (1H, br s),
7.95 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=2.4 Hz), 7.70-7.68 (2H, m),
7.56 (1H, d, J=1.8 Hz), 7.27 (1H, d, J=8.5 Hz), 6.63 (1H, d, J=1.8
Hz), 4.85-4.79 (1H, m), 4.49 (1H, dd, J=13.1, 4.6 Hz), 4.38 (1H, br
d, J=13.1 Hz), 3.89 (3H, s), 1.44 (3H, d, J=6.7 Hz).
MS spectrum (ES/APCI.sup.+): 421 (M+H), 423 (M+2+H).
(Example 17)
5-chloro-2-methoxy-N-[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2--
f][1,4]oxazepin-10-yl]benzenesulfonamide
##STR00034##
(17a) methyl (2R)-2-hydrazinylpropanoate hydrochloride
The title compound (6.82 g, yield for 3 steps: 92%) was obtained by
production according to the method described in Examples (16a)
using (2S)-2-hydroxypropanoate (5.00 g, 48.0 mmol) as a starting
material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 3.82 (1H, q, J=7.3
Hz), 3.70 (3H, s), 1.26 (3H, d, J=7.3 Hz).
(17b)
(5R)-10-bromo-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]o-
xazepine
The title compound (285 mg, yield for 3 steps: 31%) was obtained by
production according to the method described in Examples (16b)
using 1-(5-bromo-2-chloropyridin-3-yl)ethanone (825 mg, 3.34 mmol)
and methyl (2R)-2-hydrazinylpropanoate hydrochloride (672 mg, 4.35
mmol) obtained in Example (17b) as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.26 (1H, d,
J=2.4 Hz), 8.19 (1H, d, J=2.4 Hz), 7.55 (1H, d, J=1.8 Hz), 6.66
(1H, d, J=1.8 Hz), 4.95-4.88 (1H, m), 4.60 (1H, dd, J=13.1, 4.6
Hz), 4.45-4.43 (1H, m), 1.64 (3H, d, J=6.7 Hz).
(17c) tert-butyl
[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate
The title compound (290 mg, yield: 91%) was obtained by production
according to the method described in Examples (7b) using
(5R)-10-bromo-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazep-
ine (282 mg, 1.01 mmol) obtained in Example (17b) as a starting
material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.43 (1H, br
s), 8.05 (1H, d, J=2.4 Hz), 7.54 (1H, d, J=1.8 Hz), 6.71 (1H, d,
J=1.8 Hz), 6.52 (1H, br s), 4.93-4.86 (1H, m), 4.55 (1H, dd,
J=12.8, 4.6 Hz), 4.42 (1H, d, J=12.8 Hz), 1.64 (3H, d, J=6.7 Hz),
1.54 (9H, s).
(17d)
5-chloro-2-methoxy-N-[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido-
[3,2-f][1,4]oxazepin-10-yl]benzenesulfonamide
The title compound (104 mg, yield: 92%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate (85.1 mg, 0.27 mmol) obtained in Example (17c) and
5-chloro-2-methoxybenzenesulfonyl chloride (69.2 mg, 0.27 mmol) as
starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.28 (1H, br s),
7.95 (1H, d, J=2.4 Hz), 7.87 (1H, d, J=2.4 Hz), 7.75-7.63 (2H, m),
7.56 (1H, d, J=1.8 Hz), 7.27 (1H, d, J=9.2 Hz), 6.63 (1H, d, J=1.8
Hz), 4.85-4.79 (1H, m), 4.49 (1H, dd, J=12.8, 4.6 Hz), 4.38 (1H,
dd, J=12.8, 1.2 Hz), 3.89 (3H, s), 1.44 (3H, d, J=6.7 Hz).
MS spectrum (ES/APCI.sup.+): 421 (M+H), 423 (M+2+H).
(Example 18)
2-ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]benzenesulfonamide
##STR00035##
The title compound (113 mg, yield: 93%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate (90.9 mg, 0.29 mmol) obtained in Example (16c) and
5-Fluoro-2-ethoxybenzenesulfonyl chloride (74.2 mg, 0.31 mmol)
obtained in Example (9a) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.14 (1H, s),
7.94 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=2.4 Hz), 7.60 (1H, dd,
J=7.9, 3.1 Hz), 7.56 (1H, d, J=2.4 Hz), 7.50-7.45 (1H, m), 7.25
(1H, dd, J=9.2, 3.7 Hz), 6.61 (1H, d, J=2.4 Hz), 4.83-4.81 (1H, m),
4.49 (1H, dd, J=13.1, 4.6 Hz), 4.36 (1H, br d, J=13.1 Hz), 4.17
(2H, q, J=7.0 Hz), 1.44 (3H, d, J=6.7 Hz), 1.26 (3H, t, J=7.0
Hz).
MS spectrum (ES/APCI.sup.+): 419 (M+H).
(Example 19) Potassium
[(2-ethoxy-5-fluorophenyl)sulfonyl][(5S)-5-methyl-5,6-dihydropyrazolo[1,5-
-d]pyrido[3,2-f][1,4]oxazepin-10-yl]azanide (Potassium Salt of
Example 18)
##STR00036##
To a suspension of
2-ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]benzenesulfonamide (34.1 mg, 0.082 mmol)
obtained in Example 18 in ethanol (0.8 mL), a solution of 0.5 N
potassium hydroxide in ethanol (0.171 mL, 0.086 mmol) was added at
room temperature, and the mixture was stirred at room temperature
for 3.5 hours. The solvent was distillated off under reduce
pressure to obtain a crude solid. To the crude solid, ethanol was
added, the precipitated solid was collected by filtration, washed
with ethyl acetate, and then dried to obtain the title compound
(30.5 mg, yield: 82%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.66 (1H, d, J=2.4
Hz), 7.59 (1H, d, J=2.4 Hz), 7.51-7.48 (2H, m), 7.11-7.09 (1H, m),
6.96 (1H, dd, J=9.1, 4.3 Hz), 6.48 (1H, d, J=1.8 Hz), 4.75-4.72
(1H, m), 4.34 (1H, dd, J=13.4, 4.9 Hz), 4.23-4.20 (1H, m), 3.91
(2H, q, J=7.0 Hz), 1.44 (3H, d, J=6.7 Hz), 1.10 (3H, t, J=7.0
Hz).
(Example 20)
2-ethoxy-5-fluoro-N-[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]benzenesulfonamide
##STR00037##
The title compound (110 mg, yield: 91%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate (91.4 mg, 0.29 mmol) obtained in Example (17c) and
5-Fluoro-2-ethoxybenzenesulfonyl chloride (72.9 mg, 0.31 mmol)
obtained in Example (9a) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.14 (1H, s),
7.94 (1H, d, J=2.4 Hz), 7.88 (1H, d, J=2.4 Hz), 7.60 (1H, dd,
J=7.9, 3.1 Hz), 7.56 (1H, d, J=2.4 Hz), 7.52-7.43 (1H, m), 7.25
(1H, dd, J=9.5, 4.0 Hz), 6.60 (1H, d, J=2.4 Hz), 4.85-4.79 (1H, m),
4.49 (1H, dd, J=13.4, 4.3 Hz), 4.36 (1H, dd, J=13.4, 1.2 Hz), 4.17
(2H, q, J=7.0 Hz), 1.44 (3H, d, J=6.7 Hz), 1.26 (3H, t, J=7.0
Hz).
MS spectrum (ES/APCI.sup.+): 419 (M+H).
(Example 21)
5-chloro-2-methoxy-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2--
f][1,4]oxazepin-10-yl]pyridine-3-sulfonamide
##STR00038##
The title compound (104 mg, yield: 86%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate (91.0 mg, 0.29 mmol) obtained in Example (16c) and
5-chloro-2-methoxypyridine-3-sulfonyl chloride (73.1 mg, 0.30 mmol)
obtained in Example (12a) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.:10.56 (1H, br s),
8.50 (1H, d, J=2.4 Hz), 8.21 (1H, d, J=2.4 Hz), 7.98 (1H, d, J=2.4
Hz), 7.89 (1H, d, J=2.4 Hz), 7.56 (1H, d, J=2.4 Hz), 6.69 (1H, d,
J=2.4 Hz), 4.89-4.78 (1H, m), 4.50 (1H, dd, J=13.4, 4.3 Hz), 4.39
(1H, br d, J=13.4 Hz), 3.96 (3H, s), 1.45 (3H, d, J=6.7 Hz).
MS spectrum (ES/APCI.sup.+): 422 (M+H), 424 (M+2+H).
(Example 22) potassium
[(5-chloro-2-methoxypyridin-3-yl)sulfonyl][(5S)-5-methyl-5,6-dihydropyraz-
olo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl]azanide (potassium Salt
of Example 21)
##STR00039##
To a suspension of
5-chloro-2-methoxy-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2--
f][1,4]oxazepin-10-yl]pyridine-3-sulfonamide (33.8 mg, 0.080 mmol)
obtained in Example 21 in ethanol (0.8 mL), a solution of 0.5 N
potassium hydroxide in ethanol (0.168 mL, 0.084 mmol) was added at
room temperature, and the mixture was stirred at room temperature
for 4 hours. The solvent was distillated off under reduce pressure,
ethyl acetate was added thereto, and the solvent was distillated
off under reduce pressure again to obtain a crude solid. To the
crude solid, diisopropyl ether was added, the precipitated solid
was collected by filtration, washed with diisopropyl ether, and
then dried to obtain the title compound (34.7 mg, yield: 94%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 8.17 (1H, d, J=2.4
Hz), 8.01 (1H, d, J=2.4 Hz), 7.66 (1H, d, J=2.4 Hz), 7.59 (1H, d,
J=2.4 Hz), 7.49 (1H, d, J=1.8 Hz), 6.54 (1H, d, J=1.8 Hz),
4.76-4.73 (1H, m), 4.36 (1H, dd, J=13.1, 4.6 Hz), 4.25 (1H, dd,
J=13.1, 1.5 Hz), 3.76 (3H, s), 1.44 (3H, d, J=7.3 Hz).
(Example 23)
5-chloro-2-methoxy-N-[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2--
f][1,4]oxazepin-10-yl]pyridine-3-sulfonamide
##STR00040##
The title compound (107 mg, yield: 86%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
[(5R)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate (93.0 mg, 0.29 mmol) obtained in Example (17c) and
5-chloro-2-methoxypyridine-3-sulfonyl chloride (65.5 mg, 0.27 mmol)
obtained in Example (12a) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.56 (1H, br s),
8.50 (1H, d, J=3.1 Hz), 8.21 (1H, d, J=3.1 Hz), 7.98 (1H, d, J=2.4
Hz), 7.89 (1H, d, J=2.4 Hz), 7.56 (1H, d, J=2.4 Hz), 6.69 (1H, d,
J=2.4 Hz), 4.87-4.78 (1H, m), 4.51 (1H, dd, J=13.4, 4.3 Hz), 4.39
(1H, dd, J=13.4, 1.2 Hz), 3.96 (3H, s), 1.45 (3H, d, J=6.7 Hz).
MS spectrum (ES/APCI.sup.+): 422 (M+H), 424 (M+2+H).
(Example 24)
2-ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]pyridine-3-sulfonamide
##STR00041##
To a solution of tert-butyl
[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl-
]carbamate (92.1 mg, 0.29 mmol) obtained in Example (16c) in
methanol (1 mL), a 4.0 mol/L solution of hydrogen chloride in
1,4-dioxane (2 mL, 8 mmol) was added at room temperature, the
mixture was stirred at the same temperature as above for 3 hour.
The mixture was concentrated under reduce pressure. The residue was
diluted with pyridine (1.0 mL, 12 mmol),
2-ethoxy-5-fluoropyridine-3-sulfonyl chloride (83.7 mg, 0.35 mmol)
obtained in Example (14b) was added thereto at room temperature,
and the mixture was stirred at 80.degree. C. for 30 minutes in an
oil bath. After cooling, the mixture was concentrated under reduced
pressure, and the residue was purified in an automatic
chromatography apparatus (methylene chloride/methanol=99/1-91/9,
and Yamazen Co. Ltd., High-Flash.TM. column Amino, methylene
chloride/methanol=95/5-88/12). To the obtained solid, diisopropyl
ether was added, the precipitated solid was collected by
filtration, washed with diisopropyl ether, and then dried to obtain
the title compound (87.1 mg, yield: 71%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.48 (1H, br s),
8.43 (1H, d, J=3.1 Hz), 8.18 (1H, dd, J=7.3, 3.1 Hz), 7.98 (1H, d,
J=2.4 Hz), 7.92 (1H, d, J=2.4 Hz), 7.56 (1H, d, J=1.8 Hz), 6.66
(1H, d, J=1.8 Hz), 4.88-4.79 (1H, m), 4.50 (1H, dd, J=12.8, 4.3
Hz), 4.44-4.36 (3H, m), 1.45 (3H, d, J=6.7 Hz), 1.24 (3H, t, J=7.0
Hz).
MS spectrum (ES/APCI.sup.+): 420 (M+H).
(Example 25) potassium
[(2-ethoxy-5-fluoropyridin-3-yl)sulfonyl][(5S)-5-methyl-5,6-dihydropyrazo-
lo[1,5-d]pyrido[3,2-f][1,4]oxazepin-10-yl]azanide (potassium Salt
of Example 24)
##STR00042##
To a suspension of
2-ethoxy-5-fluoro-N-[(5S)-5-methyl-5,6-dihydropyrazolo[1,5-d]pyrido[3,2-f-
][1,4]oxazepin-10-yl]pyridine-3-sulfonamide (33.7 mg, 0.080 mmol)
obtained in Example 24 in ethanol (0.8 mL), a solution of 0.5 N
potassium hydroxide in ethanol (0.169 mL, 0.084 mmol) was added at
room temperature, and the mixture was stirred at the same
temperature as above for 2 hours. The solvent was distillated off
under reduce pressure, ethyl acetate was added thereto, and the
solvent was distillated off under reduce pressure again to obtain a
crude solid. To the crude solid, diisopropyl ether was added, the
precipitated solid was collected by filtration, washed with
diisopropyl ether, and then dried to obtain the title compound
(40.3 mg, yield: quantitative).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 8.07 (1H, d, J=3.0
Hz), 7.87 (1H, dd, J=7.9, 3.9 Hz), 7.72 (1H, d, J=2.4 Hz), 7.64
(1H, d, J=3.0 Hz), 7.49 (1H, d, J=1.8 Hz), 6.54 (1H, d, J=1.8 Hz),
4.77-4.73 (1H, m), 4.36 (1H, dd, J=13.1, 4.6 Hz), 4.25-4.15 (3H,
m), 1.44 (3H, d, J=6.7 Hz), 1.04 (3H, t, J=7.0 Hz).
(Example 26)
5-chloro-N-(4,5-dihydropyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazepin-9-yl)-2--
methoxybenzenesulfonamide
##STR00043##
(26a)
3-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-N-methylpropanamide
To a solution of methyl 3-hydroxypropanoate (1.50 g, 14.4 mmol) in
methylene chloride (70 mL), imidazole (1.96 g, 28.8 mmol) and
tert-butyldiphenylchlorosilane (4.36 g, 15.8 mmol) was added at
room temperature, and the mixture was stirred at the same
temperature as above for 5 days. The mixture was diluted by
addition of water, and followed by extraction with methylene
chloride. The organic layer was washed with a saturated aqueous
solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (n-hexane/ethyl acetate=100/0-40/60) to
obtain methyl 3-{[tert-butyl(diphenyl)silyl]oxy}propanoate (5.54
g). To a solution of methyl
3-{[tert-butyl(diphenyl)silyl]oxy}propanoate (5.54 g) obtained in
the above step in methanol (200 mL), a 1.0 mol/L aqueous solution
of sodium hydroxide (40 mL, 40 mmol) was added at room temperature,
and the mixture was stirred at the same temperature as above for 4
hours. The mixture was diluted by addition of a saturated aqueous
ammonium chloride under ice cooling, and followed by extraction
with ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (n-hexane/ethyl acetate=100/0-40/60) to
obtain 3-{[tert-butyl(diphenyl)silyl]oxy}propanoic acid (5.81 g).
To a solution of 3-{[tert-butyl(diphenyl)silyl]oxy}propanoic acid
(5.81 g) obtained in the above step in methylene chloride (100 mL),
N,N'-carbonyldiimidazole (3.01 g, 18.6 mmol) was added at room
temperature, and the mixture was stirred at the same temperature as
above for 1 hour. Subsequently, N,O-dimethylhydroxylamine
hydrochloride (1.81 g, 18.6 mmol) and triethylamine (2.94 mL, 21.2
mmol) was added thereto, and the mixture was stirred at room
temperature for 19 hours. The mixture was diluted by addition of
water, followed by extraction with methylene chloride. The organic
layer was washed with a saturated aqueous solution of sodium
chloride and dried over anhydrous sodium sulfate. After filtration,
the solvent was distilled off under reduced pressure, and the
residue was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=100/0-35/65) to obtain the title compound
(4.80 g, yield for 3 steps: 73%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.69-7.67 (4H,
m), 7.44-7.36 (6H, m), 4.00 (2H, t, J=6.8 Hz), 3.66 (3H, s), 3.18
(3H, s), 2.71-2.70 (2H, m), 1.04 (9H, s).
(26b)
(4E)-3,11,11-trimethyl-10,10-diphenyl-2,9-dioxa-3-aza-10-siladodec-4-
-en-6-one
To 3-{[tert-butyl(diphenyl)silyl]oxy}-N-methoxy-N-methylpropanamide
(1.50 g, 4.04 mmol) obtained in Example (26a), a 0.5 mol/L solution
of ethynylmagnesium bromide in tetrahydrofuran (10.1 mL, 5.05 mmol)
was added at room temperature, and the mixture was stirred at
50.degree. C. for 40 minutes in an oil bath. The mixture was cooled
to room temperature, a saturated aqueous solution of ammonium
chloride (10 mL) was added thereto, and the mixture was stirred at
50.degree. C. for further 40 minutes in an oil bath. The mixture
was cooled to room temperature, and followed by extraction with
ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium chloride and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (n-hexane/ethyl acetate=100/0-40/60) to
obtain the title compound (1.48 g, yield: 92%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.69-7.66 (4H,
m), 7.44-7.33 (7H, m), 5.48 (1H, d, J=12.9 Hz), 3.98 (2H, t, J=6.6
Hz), 3.64 (3H, s), 3.10 (3H, s), 2.65 (2H, t, J=6.6 Hz), 1.03 (9H,
s).
(26c) 5-bromo-2-chloro-3-hydrazinylpyridine hydrochloride
To a mixture of 5-bromo-2-chloro-pyridin-3-amine (1.50 g, 7.23
mmol) in 35% hydrochloric acid (10 mL), a solution of sodium
nitrite (500.1 mg, 7.23 mmol) in water (5 mL) was added under ice
cooling. Subsequently, the mixture was added to a solution of tin
(II) chloride dihydrate (3.26 g, 14.5 mmol) in 35% hydrochloric
acid (4 mL) under ice cooling, and the mixture was stirred at room
temperature for 1 hour. The precipitated solid was collected by
filtration, washed with 35% hydrochloric acid, and then dried to
obtain the title compound (1.465 g, yield: 78%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.07 (3H, br s),
8.63 (1H, br s), 8.12-8.11 (1H, m), 7.73-7.72 (1H, m).
(26d)
9-bromo-4,5-dihydropyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazepine
To a solution of
(4E)-3,11,11-trimethyl-10,10-diphenyl-2,9-dioxa-3-aza-10-siladodec-4-en-6-
-one (507 mg, 1.28 mmol) obtained in Example (26b) in methanol (1.5
mL), 5-bromo-2-chloro-3-hydrazinylpyridine hydrochloride (396.5 mg,
1.53 mmol) obtained in Example (26c) was added under ice cooling,
and the mixture was heated in an oil bath until reflux. And then, a
solution of sodium carbonate (257.9 mg, 2.42 mmol) in water (10 mL)
was added thereto, and the mixture was stirred under reflux for 1.5
hours. The mixture was cooled to room temperature, and concentrated
under reduce pressure. The residue was diluted by addition of
water, followed by extraction with ethyl acetate. The organic layer
was washed with a saturated aqueous solution of sodium chloride and
dried over anhydrous sodium sulfate. After filtration, the solvent
was distilled off under reduced pressure, and the residue was
purified in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-60/40) to obtain
5-bromo-3-[5-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1H-pyrazol-1-yl]-2-
-chloropyridine (390 mg). To a solution of
5-bromo-3-[5-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-1H-pyrazol-1-yl]-2-
-chloropyridine (390 mg) obtained in the above step in
tetrahydrofuran (10 mL), a 1.0 mol/L solution of tetrabutyl
ammonium fluoride in tetrahydrofuran (1.08 mL, 1.08 mmol) was added
under ice cooling, the mixture was stirred at room temperature for
16 hours.
The mixture was diluted by addition of a saturated aqueous solution
of ammonium chloride, followed by extraction with a mixed solvent
of chloroform/isopropanol=3/1. The organic layer was washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (ethyl
acetate/methanol=100/0-50/50) to obtain the title compound (60 mg,
yield for 2 steps: 18%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.75 (1H, d,
J=2.0 Hz), 8.21 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=2.0 Hz), 6.27
(1H, br s), 4.56 (2H, t, J=5.4 Hz), 3.31 (2H, t, J=5.4 Hz).
(26e) tert-butyl
4,5-dihydropyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazepin-9-ylcarbamate
The title compound (54 mg, yield: 79%) was obtained by production
according to the method described in Examples (7b) using
9-bromo-4,5-dihydropyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazepine (60.0
mg, 0.22 mmol) obtained in Example (26d) as a starting
material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.66 (1H, br
s), 8.17 (1H, br d, J=2.7 Hz), 7.65 (1H, br d, J=1.6 Hz), 6.59 (1H,
br s), 6.25-6.25 (1H, m), 4.55 (2H, t, J=5.5 Hz), 3.25 (2H, t,
J=5.5 Hz), 1.53 (9H, s).
(26f)
5-chloro-N-(4,5-dihydropyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazepin-9-y-
l)-2-methoxybenzenesulfonamide
The title compound (51 mg, yield: 70%) was obtained by production
according to the method described in Examples (7c) using tert-butyl
4,5-dihydropyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazepin-9-ylcarbamate
(54.0 mg, 0.18 mmol) obtained in Example (26e) and
5-chloro-2-methoxybenzenesulfonyl chloride (47.5 mg, 0.20 mmol) as
starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.46 (1H, br s),
8.28 (1H, d, J=2.7 Hz), 7.87 (1H, d, J=2.7 Hz), 7.71-7.66 (2H, m),
7.25 (1H, d, J=9.0 Hz), 6.38-6.37 (1H, m), 4.43 (2H, t, J=5.3 Hz),
3.89 (3H, s), 3.22 (2H, t, J=5.3 Hz).
MS spectrum (ES/APCI.sup.+): 407 (M+H), 409 (M+2+H).
(Example 27)
5-chloro-2-methoxy-N-[(9aS)-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f-
]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
##STR00044##
(27a) (2-chloro-5-nitropyridin-3-yl)
[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone
To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (300
mg, 1.48 mmol) and oxalyl chloride (0.17 mL, 2.0 mmol) in methylene
chloride (8 mL), N,N-dimethylformamide (0.05 mL) was added at room
temperature, and the mixture was stirred at the same temperature as
above for 1 hour. The reaction mixture was concentrated under
reduced pressure to prepare a crude product of
2-chloro-5-nitropyridine-3-carbonyl chloride. To a solution of
(2S)-pyrrolidin-2-ylmethanol (0.145 mL, 1.49 mmol) and
N,N-diisopropylethylamine (0.5 mL, 3 mmol) in tetrahydrofuran (4
mL), a solution of the crude product of
2-chloro-5-nitropyridine-3-carbonyl chloride in tetrahydrofuran (4
mL) was added under ice cooling, and then the reaction mixture was
stirred at room temperature for 40 minutes. The mixture was diluted
by addition of ethyl acetate, the organic layer was washed with a
saturated aqueous solution of sodium chloride, and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure and the residue was purified
in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-0/100) to obtain the title compound (338 mg, yield:
80%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.27-9.22 (1H,
m), 8.54-8.52 (1H, m), 4.41-4.39 (1H, m), 3.91-3.78 (2H, m),
3.42-3.25 (2H, m), 2.25-2.19 (1H, m), 2.09-1.78 (4H, m).
(27b)
(9aS)-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c]-
[1,4]oxazepin-5-one
To a solution of (2-chloro-5-nitropyridin-3-yl)
[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methanone (338 mg, 1.18
mmol) obtained in Example (27a) in tetrahydrofuran (60 mL), sodium
hydride (approximately 63% content, 102 mg, 2.68 mmol) was added at
room temperature, and the mixture was stirred at the same
temperature as above for 24 hours. Additional sodium hydride
(approximately 63% content, 101 mg, 2.65 mmol) was added thereto at
room temperature, and the mixture was stirred at the same
temperature as above for further 24 hours. The reaction mixture was
cooled with ice-water bath, a 2.0 mol/L aqueous solution of sodium
hydroxide was added thereto, and stirred at room temperature for 30
minutes followed by extraction with ethyl acetate. The organic
layer was washed with a saturated aqueous solution of sodium
chloride and dried over anhydrous sodium sulfate. After filtration,
the solvent was distilled off under reduced pressure, and the
residue was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=100/0-0/100) to obtain the title compound
(180 mg, yield: 61%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.48 (1H, d,
J=3.0 Hz), 9.21 (1H, d, J=3.0 Hz), 4.76 (1H, d, J=12.1 Hz), 4.25
(1H, dd, J=12.8, 7.9 Hz), 4.11-4.05 (1H, m), 3.89-3.84 (1H, m),
3.78-3.75 (1H, m), 2.39-2.32 (1H, m), 2.12-2.05 (1H, m), 2.00-1.88
(1H, m), 1.80-1.70 (1H, m).
(27c)
(9aS)-3-amino-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c]-
[1,4]oxazepin-5-one
To a mixture of (9aS)-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one (180 mg, 0.72
mmol) obtained in Example (27b) in tetrahydrofuran (3 mL) and
methanol (3 mL), nickel(II) chloride hexahydrate (358 mg, 1.51
mmol) was added. Subsequently, the mixture was cooled in an ice
water bath. Sodium borohydride (107 mg, 2.83 mmol) was added
thereto, the mixture was stirred at room temperature for 50
minutes. The reaction mixture was diluted by addition of acetone
and a saturated aqueous solution of sodium bicarbonate, further
Celite 545.RTM. (approximately 0.7 g) was added thereto, and the
mixture was stirred at room temperature for further 30 minutes. The
reaction mixture was filtered, the filtrate was extracted with a
mixed solvent of ethyl acetate and tetrahydrofuran, and the organic
layer was dried over anhydrous sodium sulfate. After filtration,
the solvent was distilled off under reduced pressure, and the
residue was purified in an automatic chromatography apparatus
(ethyl acetate/methanol=100/0-80/20) to obtain the title compound
(140 mg, yield: 89%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.88-7.87 (2H,
m), 4.55-4.52 (1H, m), 4.05-3.98 (2H, m), 3.77-3.73 (2H, m), 3.60
(2H, br s), 2.24-2.20 (1H, m), 2.04-1.88 (2H, m), 1.73-1.64 (1H,
m).
(27d)
5-chloro-2-methoxy-N-[(9aS)-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[-
3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
To a mixture of (9aS)-3-amino-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one (140 mg, 0.64
mmol) obtained in Example (27c) and pyridine (3 mL, 37 mmol),
5-chloro-2-methoxybenzenesulfonyl chloride (170 mg, 0.70 mmol) was
added, and the mixture was stirred at 80.degree. C. for 1 hour in
an oil bath. The reaction mixture was cooled, and then concentrated
under reduced pressure. The residue was purified in an automatic
chromatography apparatus (ethyl acetate/methanol=100/0-80/20). To
the obtained solid, diisopropyl ether was added, the precipitated
solid was collected by filtration, and then dried to obtain the
title compound (172 mg, yield: 63%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.32 (1H, d,
J=3.0 Hz), 8.24 (1H, d, J=3.0 Hz), 7.73 (1H, d, J=2.7 Hz), 7.46
(1H, dd, J=8.8, 2.7 Hz), 7.03 (1H, br s), 7.00 (1H, d, J=8.8 Hz),
4.60 (1H, d, J=11.5 Hz), 4.04-3.98 (5H, m), 3.80-3.66 (2H, m),
2.29-2.23 (1H, m), 2.06-1.84 (2H, m), 1.70-1.65 (1H, m).
MS spectrum (ES/APCI.sup.+): 424 (M+H), 426 (M+2+H)
(Example 28)
5-chloro-2-methoxy-N-[(9aR)-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f-
]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
##STR00045##
(28a)
(2-chloro-5-nitropyridin-3-yl)[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl-
]methanone
The title compound (594 mg, yield: 71%) was obtained by production
according to the method described in Example (27a) using
2-chloro-5-nitropyridine-3-carboxylic acid (500 mg, 2.49 mmol) and
(2R)-pyrrolidin-2-ylmethanol (0.258 mg, 2.55 mmol) as starting
materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.27-9.22 (1H,
m), 8.54-8.52 (1H, m), 4.41-4.39 (1H, m), 3.91-3.78 (2H, m),
3.42-3.25 (2H, m), 2.25-2.19 (1H, m), 2.09-1.78 (4H, m).
(28b)
(9aR)-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c]-
[1,4]oxazepin-5-one
To a solution of
(2-chloro-5-nitropyridin-3-yl)[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]meth-
anone (594 mg, 2.08 mmol) obtained in Example (28a) in
tetrahydrofuran (100 mL), a ca. 1.9 mol/L solution of sodium
bis(trimethylsilyl)amide in tetrahydrofuran (1.6 mL, 3.0 mmol) was
added under ice cooling, and the mixture was stirred at the same
temperature for 1 hour. The mixture was diluted by addition of a
saturated aqueous solution of sodium chloride followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride, dried over anhydrous
sodium sulfate. After filtration, the solvent was distillated off
under reduced pressure, and the residue was purified in an
automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-20/80) to obtain the title compound (385 mg, yield:
52%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.48 (1H, d,
J=3.0 Hz), 9.21 (1H, d, J=3.0 Hz), 4.76 (1H, d, J=12.1 Hz), 4.25
(1H, dd, J=12.8, 7.9 Hz), 4.11-4.05 (1H, m), 3.89-3.84 (1H, m),
3.78-3.75 (1H, m), 2.39-2.32 (1H, m), 2.12-2.05 (1H, m), 2.00-1.88
(1H, m), 1.80-1.70 (1H, m).
(28c)
(9aR)-3-amino-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c]-
[1,4]oxazepin-5-one
The title compound (341 mg, yield: quantitative) was obtained by
production according to the method described in Example (27c) using
(9aR)-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]-
oxazepin-5-one (385 mg, 1.54 mmol) obtained in Example (28b) as a
starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.88-7.87 (2H,
m), 4.55-4.52 (1H, m), 4.05-3.98 (2H, m), 3.77-3.73 (2H, m), 3.60
(2H, br s), 2.24-2.20 (1H, m), 2.04-1.88 (2H, m), 1.73-1.64 (1H,
m).
(28d)
5-chloro-2-methoxy-N-[(9aR)-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[-
3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
The title compound (178 mg, yield: 58%) was obtained by production
according to the method described in Example (27d) using
(9aR)-3-amino-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one (165 mg, 0.75
mmol) obtained in Example (28c) and
5-chloro-2-methoxybenzenesulfonyl chloride (60.8 mg, 0.25 mmol) as
starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.32 (1H, d,
J=3.0 Hz), 8.24 (1H, d, J=3.0 Hz), 7.73 (1H, d, J=2.7 Hz), 7.46
(1H, dd, J=8.8, 2.7 Hz), 7.03 (1H, br s), 7.00 (1H, d, J=8.8 Hz),
4.60 (1H, d, J=11.5 Hz), 4.04-3.98 (5H, m), 3.80-3.66 (2H, m),
2.29-2.23 (1H, m), 2.06-1.84 (2H, m), 1.70-1.65 (1H, m).
MS spectrum (ES/APCI.sup.+): 424 (M+H), 426 (M+2+H).
(Example 29)
5-chloro-N-[(8R,9aS)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
##STR00046##
(29a)
(2-chloro-5-nitropyridin-3-yl)[(2S,4R)-4-hydroxy-2-(hydroxymethyl)py-
rrolidin-1-yl]methanone
The title compound (540 mg, yield: 77%) was obtained by production
according to the method described in Example (27a) using
2-chloro-5-nitropyridine-3-carboxylic acid (470 mg, 2.32 mmol) and
(3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol (0.354 mg, 2.30 mmol) as
starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 9.28 (1H, d, J=3.0
Hz), 8.79-8.74 (1H, m), 5.00-4.24 (4H, m), 3.79-2.96 (4H, m),
2.08-1.97 (2H, m).
(29b)
(8R,9aS)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]p-
yrrolo[2,1-c][1,4]oxazepin-5-one
The title compound (182 mg, yield: 78%) was obtained by production
according to the method described in Example (28b) using
(2-chloro-5-nitropyridin-3-yl)
[(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-1-yl]methanone (265
mg, 0.88 mmol) obtained in Example (29a) as a starting
material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.51 (1H, d,
J=2.4 Hz), 9.23 (1H, d, J=2.4 Hz), 4.80 (1H, d, J=12.8 Hz), 4.63
(1H, d, J=3.6 Hz), 4.47-4.40 (1H, m), 4.27-4.24 (1H, m), 3.95 (1H,
dd, J=13.7, 3.6 Hz), 3.83 (1H, dd, J=13.7, 2.1 Hz), 2.37-2.33 (1H,
m), 1.90-1.81 (2H, m).
(29c) (8R,9aS)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
The title compound (134 mg, yield: 84%) was obtained by production
according to the method described in Example (27c) using
(8R,9aS)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (180 mg, 0.68 mmol) obtained in Example
(29b) as a starting material.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 7.84 (1H, d,
J=3.0 Hz), 7.81 (1H, d, J=3.0 Hz), 4.55 (1H, dd, J=11.5, 1.8 Hz),
4.44 (1H, br s), 4.21-4.08 (2H, m), 3.77-3.73 (2H, m), 2.22-2.19
(1H, m), 1.91-1.85 (1H, m).
(29d)
5-chloro-N-[(8R,9aS)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (96 mg, yield: 78%) was obtained by production
according to the method described in Example (27d) using
(8R,9aS)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (66 mg, 0.28 mmol) obtained in Example
(29c) and 5-chloro-2-methoxybenzenesulfonyl chloride (77 mg, 0.32
mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.28 (1H, br s),
8.23 (1H, br s), 8.08 (1H, br s), 7.64 (2H, br s), 7.25 (1H, br s),
5.07 (1H, br s), 4.53-4.52 (1H, m), 4.26 (1H, br s), 4.13-4.05 (2H,
m), 3.89 (3H, s), 3.64-3.46 (2H, m), 2.04 (1H, br s), 1.72 (1H, br
s).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H).
(Example 30)
5-chloro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
##STR00047##
(30a)
(2-chloro-5-nitropyridin-3-yl)[(2R,4S)-4-hydroxy-2-(hydroxymethyl)py-
rrolidin-1-yl]methanone
To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (280
mg, 1.38 mmol) and oxalyl chloride (0.154 mL, 1.80 mmol) in
methylene chloride (8 mL), N,N-dimethylformamide (0.05 mL) was
added at room temperature, and the mixture was stirred at the same
temperature as above for 1 hour. The reaction mixture was
concentrated under reduced pressure to prepare a crude product of
2-chloro-5-nitropyridine-3-carbonyl chloride. To a mixture of
(3S,5R)-5-(hydroxymethyl)pyrrolidin-3-ol (212 mg, 1.38 mmol) and
N,N-diisopropylethylamine (1 mL, 5.9 mmol) in tetrahydrofuran (4
mL), a solution of the crude product of
2-chloro-5-nitropyridine-3-carbonyl chloride in tetrahydrofuran (4
mL) was added under ice cooling, and then the reaction mixture was
stirred at room temperature for 80 minutes. The mixture was
concentrated under reduced pressure and the residue was purified in
an automatic chromatography apparatus (ethyl
acetate/methanol=100/0-85/15) to obtain the title compound (243 mg,
yield: 80%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 9.28 (1H, d, J=3.0
Hz), 8.79-8.74 (1H, m), 5.00-4.24 (4H, m), 3.79-2.96 (4H, m),
2.08-1.97 (2H, m).
(30b) (8S,9aR)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
A 1.09 mol/L solution of sodium bis(trimethylsilyl)amide in
tetrahydrofuran (1.7 mmol, 1.9 mmol) was diluted with
tetrahydrofuran (50 mL), a solution of
(2-chloro-5-nitropyridin-3-yl)[(2R,4S)-4-hydroxy-2-(hydroxymethyl)pyrroli-
din-1-yl]methanone (243 mg, 0.80 mmol) obtained in Example (30a) in
tetrahydrofuran (10 mL) was added thereto under ice cooling, and
the mixture was stirred at the same temperature for 40 minutes. The
mixture was diluted by addition of a saturated aqueous solution of
sodium chloride followed by extraction with ethyl acetate. The
organic layer was washed with a saturated aqueous solution of
sodium chloride, dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (ethyl acetate/methanol=100/0-85/15) to obtain the title
compound (77.4 mg, yield: 36%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.51 (1H, d,
J=2.4 Hz), 9.23 (1H, d, J=2.4 Hz), 4.80 (1H, d, J=12.8 Hz), 4.63
(1H, d, J=3.6 Hz), 4.47-4.40 (1H, m), 4.27-4.24 (1H, m), 3.95 (1H,
dd, J=13.7, 3.6 Hz), 3.83 (1H, dd, J=13.7, 2.1 Hz), 2.37-2.33 (1H,
m), 1.90-1.81 (2H, m).
(30c) (8S,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
A mixture of
(8S,9aR)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (77.4 mg, 0.29 mmol) obtained in
Example (30b) and 10% palladium carbon (water content: 54.6%, 20
mg) in methanol (6 mL) was stirred at room temperature for 1.5
hours at normal pressure under the hydrogen atmosphere. Hydrogen in
the reaction container was replaced with nitrogen, and then, the
reaction mixture was filtered through pad of Celite 545.RTM.. The
solvent in the filtrate was distilled off under reduced pressure to
obtain the title compound (64.2 mg, yield: 94%).
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 7.84 (1H, d,
J=3.0 Hz), 7.81 (1H, d, J=3.0 Hz), 4.55 (1H, dd, J=11.5, 1.8 Hz),
4.44 (1H, br s), 4.21-4.08 (2H, m), 3.77-3.73 (2H, m), 2.22-2.19
(1H, m), 1.91-1.85 (1H, m).
(30d)
5-chloro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (83.7 mg, yield: 70%) was obtained by production
according to the method described in Example (27d) using
(8S,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (64.2 mg, 0.27 mmol) obtained in
Example (30c) and 5-chloro-2-methoxybenzenesulfonyl chloride (70.5
mg, 0.29 mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.28 (1H, br s),
8.23 (1H, br s), 8.08 (1H, br s), 7.64 (2H, br s), 7.25 (1H, br s),
5.07 (1H, br s), 4.53-4.52 (1H, m), 4.26 (1H, br s), 4.13-4.05 (2H,
m), 3.89 (3H, s), 3.64-3.46 (2H, m), 2.04 (1H, br s), 1.72 (1H, br
s).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H).
(Example 31)
5-fluoro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
##STR00048##
The title compound (211 mg, yield: 65%) was obtained by production
according to the method described in Example (27d) using
(8S,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (180 mg, 0.76 mmol) obtained in Example
(30c) and 5-fluoro-2-methoxybenzenesulfonyl chloride (190 mg, 0.85
mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.25 (1H, br s),
8.23 (1H, d, J=2.4 Hz), 8.09 (1H, d, J=2.4 Hz), 7.51-7.46 (2H, m),
7.26-7.24 (1H, m), 5.06 (1H, br s), 4.52 (1H, d, J=11.5 Hz), 4.25
(1H, br s), 4.09-4.04 (2H, m), 3.88 (3H, s), 3.63 (1H, dd, J=13.1,
6.5 Hz), 3.45 (1H, d, J=12.8 Hz), 2.05 (1H, dd, J=13.1, 5.8 Hz),
1.75-1.68 (1H, m).
MS spectrum (ES/APCI.sup.+): 424 (M+H).
(Example 32)
5-chloro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de
##STR00049##
(32a) 5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride
To a suspension of 5-chloro-2-(trifluoromethoxy)aniline (5.00 g,
23.6 mmol) and dibenzyl disulfide (4.66 g, 18.9 mmol) in
acetonitrile (75 mL), isoamyl nitrite (3.46 mL, 26.0 mmol) was
slowly added at 60.degree. C. in an oil bath, and the mixture was
stirred at the same temperature as above for 2 hours. The reaction
mixture was cooled and then concentrated under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (n-hexane/ethyl acetate=100/0-95/5) to prepare
2-(benzylsulfanyl)-4-chlorophenyl trifluoromethyl ether (3.86 g,
yield: 51%). To a mixture of 2-(benzylsulfanyl)-4-chlorophenyl
trifluoromethyl ether (4.84 g, 15.2 mmol) obtained in the above
step, acetic acid (4.5 mL) and water (3 mL) in acetonitrile (120
mL), 1,3-dichloro-5,5-dimethylhydantoin (5.98 g, 30.4 mmol) was
added under ice cooling, and the mixture was stirred at the same
temperature as above for 3 hours. The mixture was diluted by
addition of a saturated aqueous solution of sodium bicarbonate,
extracted with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (hexane/ethyl
acetate=100/0-85/15) to obtain the title compound (3.64 g, yield:
81%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.09 (1H, d,
J=2.3 Hz), 7.75 (1H, dd, J=9.0, 2.7 Hz), 7.50-7.47 (1H, m).
(32b)
5-chloro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulf-
onamide
To a mixture of
(8S,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (562 mg, 2.39 mmol) obtained in Example
(30c) and pyridine (3.86 mL, 47.8 mmol),
5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride (740 mg, 2.51
mmol) obtained in Example (32a) was added, and the mixture was
stirred at 80.degree. C. for 2 hours in an oil bath. After cooling,
additional 5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride
(141 mg, 0.48 mmol) was added thereto, and the mixture was stirred
at 80.degree. C. for further 2 hours in an oil bath. The reaction
mixture was cooled, and then concentrated under reduced pressure.
The residue was purified in an automatic chromatography apparatus
(ethyl acetate/methanol=100/0-90/10). To the obtained solid,
ethanol was added, the precipitated solid was collected by
filtration, and then dried to obtain the title compound (844 mg,
yield: 72%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.78 (1H, br s),
8.20 (1H, d, J=2.7 Hz), 8.13 (1H, d, J=2.7 Hz), 7.90-7.88 (2H, m),
7.64-7.61 (1H, m), 5.08 (1H, br s), 4.56 (1H, d, J=12.1 Hz), 4.26
(1H, br s), 4.14-4.06 (2H, m), 3.65 (1H, dd, J=12.9, 3.9 Hz), 3.45
(2H, d, J=12.9 Hz), 2.07 (1H, dd, J=12.9, 6.6 Hz), 1.77-1.70 (1H,
m).
MS spectrum (ES/APCI.sup.+): 494 (M+H), 496 (M+2+H).
(Example 33) Potassium
{[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}[(8S,9aR)-8-hydroxy-5-oxo--
8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]a-
zanide (Potassium Salt of Example 32)
##STR00050##
To a suspension of
5-chloro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de (26.8 mg, 0.054 mmol) obtained in Example (32b) in ethanol (0.5
mL), a 0.5 mol/L solution of potassium hydroxide in ethanol (0.119
mL, 0.060 mmol) was added at room temperature, and the mixture was
stirred at room temperature for 3 hours. The mixture was
concentered under reduced pressure, diisopropyl ether was added
thereto, the precipitated solid was collected by filtration, and
then dried to obtain the title compound (27.2 mg, yield: 94%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.79-7.78 (2H, m),
7.74 (1H, d, J=2.7 Hz), 7.51 (1H, dd, J=8.6, 2.7 Hz), 7.34 (1H, dd,
J=8.6, 1.2 Hz), 5.03 (1H, d, J=3.5 Hz), 4.38 (1H, d, J=9.4 Hz),
4.25 (1H, br s), 3.96-3.95 (2H, m), 3.60-3.57 (1H, m), 3.48 (1H, d,
J=12.1 Hz), 2.03-1.99 (1H, m), 1.74-1.67 (1H, m).
(Example 34)
5-fluoro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de
##STR00051##
(34a) 5-fluoro-2-(trifluoromethoxy)benzenesulfonyl chloride
The title compound (0.82 g, yield for 2 steps: 29%) was obtained by
production according to the method described in Example (32a) using
5-fluoro-2-(trifluoromethoxy)aniline (2.00 g, 10.3 mmol).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.84 (1H, dd,
J=6.8, 2.9 Hz), 7.56-7.47 (2H, m).
(34b)
5-fluoro-N-[(8S,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulf-
onamide
The title compound (81 mg, yield: 67%) was obtained by production
according to the method described in Example (27d) using
(8S,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (60 mg, 0.26 mmol) obtained in Example
(30c) and 5-fluoro-2-(trifluoromethoxy)benzenesulfonyl chloride (78
mg, 0.28 mmol) obtained in Example (34a) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.75 (1H, br s),
8.20 (1H, d, J=2.9 Hz), 8.12 (1H, d, J=2.9 Hz), 7.74-7.73 (1H, m),
7.67-7.66 (2H, m), 5.06 (1H, d, J=3.4 Hz), 4.56 (1H, d, J=12.0 Hz),
4.26 (1H, d, J=3.4 Hz), 4.13 (1H, dd, J=12.0, 8.1 Hz), 4.08-4.05
(1H, m), 3.64 (1H, dd, J=12.7, 3.9 Hz), 3.45 (1H, dd, J=12.7, 1.5
Hz), 2.08-2.05 (1H, m), 1.75-1.72 (1H, m).
MS spectrum (ES/APCI.sup.+): 478 (M+H)
(Example 35)
5-chloro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
##STR00052##
(35a) tert-butyl (2R,4R)-4-hydroxy-2-(hydroxymethyl)
pyrrolidine-1-carboxylate
To a solution of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline
(820 mg, 3.55 mmol) and triethylamine (0.516 mL, 3.72 mmol) in
tetrahydrofuran (30 mL), isobutyl chloroformate (0.489 mL, 3.72
mmol) was added under ice cooling, and the mixture was stirred at
the same temperature as above for 30 minutes. The insoluble matter
was filtered off, and the residue was washed with tetrahydrofuran.
The filtrate and washing were combined, sodium borohydride (268 mg,
7.09 mmol) was added thereto under ice cooling followed by addition
of water (3 mL), and the mixture was stirred at the same
temperature as above for 30 minutes. The mixture was diluted with
addition of water, and followed by extraction with ethyl acetate.
The organic layer was washed with a saturated aqueous solution of
sodium chloride, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, the residue was
purified in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-0/100) to obtain the title compound (725 mg, yield:
94%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 4.42-3.95 (4H,
m), 3.59-3.47 (4H, m), 2.38-2.35 (1H, m), 1.94-1.83 (1H, m), 1.47
(9H, s).
(35b) (3R,5R)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride
To a solution of tert-butyl
(2R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (725
mg, 3.34 mmol) obtained in Example (35a) in methanol (18 mL), a 4.0
mol/L solution of hydrochloric acid in 1,4-dioxane (12 mL, 48 mmol)
was added at room temperature, and the mixture was stirred at the
same temperature for 1 hour. The solvent was distilled off under
reduced pressure to obtain a crude product of the title compound
(513 mg, yield: quantitative).
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 4.52-4.51 (1H,
m), 3.84-3.70 (3H, m), 3.24-3.23 (2H, m), 2.37-2.30 (1H, m),
1.74-1.68 (1H, m).
(35c)
(2-chloro-5-nitropyridin-3-yl)[(2R,4R)-4-hydroxy-2-(hydroxymethyl)py-
rrolidin-1-yl]methanone
To a suspension of 2-chloro-5-nitropyridine-3-carboxylic acid (676
mg, 3.34 mmol) in methylene chloride (15 mL), oxalyl chloride
(0.358 mL, 4.17 mmol) and N,N-dimethylformamide (0.128 mL, 0.128
mmol) was added at room temperature, and the mixture was stirred at
the same temperature as above for 1.5 hours. The reaction mixture
was concentrated under reduced pressure to prepare a crude product
of 2-chloro-5-nitropyridine-3-carbonyl chloride. To a mixture of
(3R,5R)-5-(hydroxymethyl)pyrrolidin-3-ol hydrochloride (513 mg,
3.34 mmol) obtained in Example (35b) and N,N-diisopropylethylamine
(2.91 mL, 16.7 mmol) in N,N-dimethylformamide (15 mL), a solution
of the crude product of 2-chloro-5-nitropyridine-3-carbonyl
chloride in N,N-dimethylformamide (5 mL) was added under ice
cooling, and then the reaction mixture was stirred at room
temperature for 1 hour. The mixture was concentrated under reduced
pressure and the residue was purified in an automatic
chromatography apparatus (ethyl acetate/methanol=100/0-90/10) to
obtain the title compound (966 mg, yield: 96%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.25-9.24 (1H,
m), 8.59 (1H, br s), 5.27 (1H, br s), 4.76-4.33 (4H, m), 4.06-3.30
(3H, m), 2.53-2.48 (1H, m), 2.07-2.01 (1H, m).
(35d) (8R,9aR)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
To a solution of
(2-chloro-5-nitropyridin-3-yl)[(2R,4R)-4-hydroxy-2-(hydroxymethyl)pyrroli-
din-1-yl]methanone (966 mg, 3.20 mmol) obtained in Example (35c) in
N,N-dimethylformamide (160 mL), potassium carbonate (1.33 g, 9.61
mmol) was added at room temperature, and the mixture was stirred at
the same temperature for 3 days. The insoluble matter was filtered
off, and the residue was washed with ethyl acetate. The filtrate
and the washes were combined, the solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (ethyl acetate/methanol=100/0-85/15) to
obtain the title compound (626 mg, yield: 74%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.38 (1H, d,
J=2.7 Hz), 9.23 (1H, d, J=2.7 Hz), 4.73-4.68 (2H, m), 4.59-4.57
(1H, m), 4.16-4.12 (2H, m), 3.74 (1H, dd, J=13.3, 4.3 Hz),
2.62-2.55 (1H, m), 2.04-2.01 (2H, m).
(35e) (8R,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
A mixture of
(8R,9aR)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (243 mg, 0.92 mmol) obtained in Example
(35d) and 10% palladium carbon (water content: 54.6%, 100 mg) in
methanol (15 mL) was stirred at room temperature for 5 hours at
normal pressure under the hydrogen atmosphere. Hydrogen in the
reaction container was replaced with nitrogen, and then, the
reaction mixture was filtered through pad of Celite 545.RTM.. The
solvent in the filtrate was distilled off under reduced pressure to
obtain the title compound (208 mg, yield: 97%).
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 7.79 (1H, d,
J=3.1 Hz), 7.61 (1H, d, J=3.1 Hz), 4.55-4.53 (1H, m), 4.47-4.45
(1H, m), 4.41 (1H, dd, J=11.0, 3.1 Hz), 4.08-4.01 (1H, m),
3.79-3.75 (1H, m), 3.70 (1H, dd, J=12.9, 4.7 Hz), 2.43-2.36 (1H,
m), 1.85-1.80 (1H, m).
(35f)
5-chloro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (165 mg, yield: 74%) was obtained by production
according to the method described in Example (27d) using
(8R,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (120 mg, 0.51 mmol) obtained in Example
(35e) and 5-chloro-2-methoxybenzenesulfonyl chloride (135 mg, 0.56
mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.30 (1H, br s),
7.67 (1H, dd, J=9.0, 2.3 Hz), 7.64 (1H, d, J=2.3 Hz), 7.26 (1H, d,
J=9.0 Hz), 5.21 (1H, d, J=3.5 Hz), 4.47-4.44 (1H, m), 4.34 (1H, t,
J=10.2 Hz), 4.27-4.25 (1H, m), 3.97-3.93 (1H, m), 3.88 (3H, s),
3.55-3.54 (2H, m), 2.31-2.26 (1H, m), 1.71-1.65 (1H, m).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H).
(Example 36)
5-fluoro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
##STR00053##
The title compound (135 mg, yield: 85%) was obtained by production
according to the method described in Example (27d) using
(8R,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (88 mg, 0.37 mmol) obtained in Example
(35e) and 5-fluoro-2-methoxybenzenesulfonyl chloride (92.4 mg, 0.41
mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.28 (1H, br s),
8.09-8.08 (2H, m), 7.51-7.47 (2H, m), 7.26-7.23 (1H, m), 5.20 (1H,
d, J=3.1 Hz), 4.46-4.44 (1H, m), 4.33-4.26 (2H, m), 3.94 (1H, dd,
J=12.5, 9.4 Hz), 3.87 (3H, s), 3.55-3.54 (2H, m), 2.32-2.28 (1H,
m), 1.69-1.65 (1H, m).
MS spectrum (ES/APCI.sup.+): 424 (M+H).
(Example 37)
5-chloro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de
##STR00054##
To a mixture of
(8R,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (44.0 mg, 0.19 mmol) obtained in
Example (35e) and pyridine (2 mL, 25 mmol),
5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride (60 mg, 0.20
mmol) obtained in Example (32a) was added, and the mixture was
stirred at 80.degree. C. for 4.5 hours in an oil bath. The reaction
mixture was cooled, and then concentrated under reduced pressure.
The residue was purified in an automatic chromatography apparatus
(ethyl acetate/methanol=100/0-90/10) to obtain the title compound
(49.2 mg, yield: 53%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.80 (1H, br s),
8.12 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=2.4 Hz), 7.90-7.88 (2H, m),
7.63-7.62 (1H, m), 5.22 (1H, d, J=3.0 Hz), 4.49 (1H, dd, J=11.8,
1.8 Hz), 4.36 (1H, dd, J=11.8, 5.9 Hz), 4.27-4.25 (1H, m),
3.97-3.94 (1H, m), 3.63-3.50 (3H, m), 2.34-2.30 (1H, m), 1.73-1.67
(1H, m).
MS spectrum (ES/APCI.sup.+): 494 (M+H), 496 (M+2+H)
(Example 38) Potassium
{[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}[(8R,9aR)-8-hydroxy-5-oxo--
8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]a-
zanide (Potassium Salt of Example 37)
To a suspension of
5-chloro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de (807 mg, 1.63 mmol) obtained in Example 37 in ethanol (20 mL), a
0.5 mol/L solution of potassium hydroxide in ethanol (3.26 mL, 1.63
mmol) was added at room temperature, and the mixture was stirred at
room temperature for 1.5 hour. The mixture was concentered under
reduced pressure, diisopropyl ether (10 mL) and ethyl acetate (5
mL) were added thereto, the precipitated solid was collected by
filtration to obtain the title compound (743 mg, yield: 86%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.78-7.76 (2H, m),
7.63 (1H, br s), 7.54 (1H, br d, J=7.8 Hz), 7.36 (1H, br d, J=7.8
Hz), 5.15 (1H, d, J=2.7 Hz), 4.33-4.26 (3H, m), 3.86-3.82 (1H, m),
3.53-3.52 (2H, m), 2.27-2.20 (1H, m), 1.65-1.62 (1H, m).
(Example 39)
5-fluoro-N-[(8R,9aR)-8-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de
The title compound (92 mg, yield: 91%) was obtained by production
according to the method described in Example (27d) using
(8R,9aR)-3-amino-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (50 mg, 0.21 mmol) obtained in Example
(35e) and 5-fluoro-2-(trifluoromethoxy)benzenesulfonyl chloride (71
mg, 0.26 mmol) obtained in Example (34a) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.79 (1H, br s),
8.12 (1H, d, J=2.4 Hz), 8.05 (1H, d, J=2.4 Hz), 7.75-7.73 (1H, m),
7.68-7.67 (2H, m), 5.21 (1H, d, J=3.4 Hz), 4.49 (1H, dd, J=11.7,
2.0 Hz), 4.35 (1H, dd, J=11.7, 8.8 Hz), 4.26 (1H, br s), 3.97-3.96
(1H, m), 3.55-3.52 (2H, m), 2.34-2.29 (1H, m), 1.70-1.68 (1H,
m).
MS spectrum (ES/APCI.sup.+): 478 (M+H).
(Example 40)
5-chloro-N-[(9R,9aS)-9-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
(40a) (3R)-1-(tert-butoxycarbonyl)-3-hydroxy-D-proline
To a solution of (3R)-3-hydroxy-D-proline (2.0 g, 15 mmol) in
tetrahydrofuran (50 mL), a saturated aqueous solution of sodium
bicacrbonate (30 mL) was added at room temperature, followed by
addition of di-tert-butyl dicarbonate (4.9 g, 22 mmol), and the
mixture was stirred at the same temperature as above for 24 hours.
Most of the organic solvent was distilled off under reduced
pressure, the concentrated mixture was washed with ethyl acetate.
The aqueous layer was diluted by addition of a 1.0 mol/L
hydrochloric acid until it became acidic, followed by extraction
with ethyl acetate four times. The organic layer was dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure to obtain the title compound
(3 g, yield: 85%).
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 12.66 (1H, br s),
5.44 (1H, br s), 4.24-4.20 (1H, m), 3.95 (0.4H, s), 3.90 (0.6H, s),
3.45-3.31 (2H, m), 1.90-1.84 (1H, m), 1.77-1.70 (1H, m), 1.40
(3.6H, s), 1.34 (5.4H, s).
(40b) (2S,3R)-2-(hydroxymethyl) pyrrolidin-3-ol hydrochloride
A crude product of the title compound (247 mg, yield: 36% for 2
steps) was obtained by production according to the method described
in Examples (35a) and (35b) using
(3R)-1-(tert-butoxycarbonyl)-3-hydroxy-D-proline (1 g, 4.3 mmol)
obtained in Example (40a) as a starting material.
(40c) (9R,9aS)-9-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
The title compound (253 mg, yield: 63% for 2 steps) was obtained by
production according to the method described in Examples (35c) and
(35d) using 2-chloro-5-nitropyridine-3-carboxylic acid (305 mg,
1.51 mmol) and (2S,3R)-2-(hydroxymethyl)pyrrolidin-3-ol
hydrochloride (0.24 g, 1.57 mmol) obtained in Example (40b) as
starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.50 (1H, d,
J=3.0 Hz), 9.22 (1H, d, J=3.0 Hz), 5.02 (1H, br d, J=12.1 Hz), 4.24
(1H, dd, J=12.1, 8.5 Hz), 4.16-4.12 (1H, m), 3.89-3.78 (3H, m),
3.06 (1H, d, J=5.5 Hz), 2.38-2.31 (1H, m), 2.03-1.99 (1H, m).
(40d) (9R,9aS)-3-amino-9-hydroxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
A crude product of the title compound (120 mg, yield: 53%) was
obtained by production according to the method described in Example
(30c) using
(9R,9aS)-9-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (253 mg, 0.95 mmol) obtained in Example
(40c) as a starting material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.70 (1H, d, J=3.0
Hz), 7.51 (1H, d, J=3.0 Hz), 5.37 (1H, d, J=4.3 Hz), 5.21 (2H, br
s), 4.45 (1H, dd, J=11.5, 3.0 Hz), 3.97-3.93 (2H, m), 3.62-3.48
(3H, m), 2.11-2.08 (1H, m), 1.80-1.77 (1H, m).
(40e)
5-chloro-N-[(9R,9aS)-9-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (49.6 mg, yield: 49%) was obtained by production
according to the method described in Example (27d) using
(9R,9aS)-3-amino-9-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (54.1 mg, 0.23 mmol) obtained in
Example (40d) and 5-chloro-2-methoxybenzenesulfonyl chloride (70
mg, 0.29 mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.29 (1H, br s),
8.22 (1H, d, J=2.4 Hz), 8.08 (1H, d, J=2.4 Hz), 7.67-7.64 (2H, m),
7.26 (1H, d, J=9.1 Hz), 5.56 (1H, br s), 4.61 (1H, dd, J=12.1, 1.2
Hz), 4.11 (1H, dd, J=12.1, 9.1 Hz), 3.90-3.88 (4H, m), 3.57-3.47
(3H, m), 3.37 (1H, br s), 2.09-2.06 (1H, m), 1.77-1.72 (1H, m).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H).
(Example 41)
5-chloro-N-[(9S,9aS)-9-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
(41a) tert-butyl (2S,3S)-3-hydroxy-2-(hydroxymethyl)
pyrrolidine-1-carboxylate
To a solution of (3S)-1-(tert-butoxycarbonyl)-3-hydroxy-D-proline
(988 mg, 4.27 mmol) in a mixed solvent of tetrahydrofuran (20 mL)
and methanol (20 mL), a ca. 0.60 mol/L solution of
trimethylsiliydiazomethane (14 mL, 8.6 mmol) was added under ice
cooling, and the mixture was stirred at room temperature for 2
hours. The solvent was distilled off under reduced pressure, and
the residue was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=100/0-0/100) to obtain 1-tert-butyl
2-methyl (2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.117 g).
To a solution of l-tert-butyl 2-methyl
(2R,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.117 g) obtained
in the above step in tetrahydrofuran (40 mL), a 2.0 mol/L solution
of lithium borohydride in tetrahydrofuran (2.7 mL, 5.5 mmol) was
added under ice cooling, and the mixture was stirred at room
temperature for 4 days. The mixture was diluted by addition of a
saturated aqueous solution of ammonium chloride followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride, and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-0/100) to obtain the title compound (793 mg, yield:
80% for 2 steps).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 4.50 (1H, br
s), 4.00-3.78 (4H, m), 3.48-3.46 (2H, m), 2.30-1.87 (2H, m), 1.47
(9H, s).
(41b) (2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol hydrochloride
A crude product of the title compound (561 mg, yield: quantitative)
was obtained by production according to the method described in
Example (35b) using tert-butyl
(2S,3S)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (793
mg, 3.65 mmol) obtained in Example (41a) as a starting
material.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 4.44-4.43 (1H,
m), 3.94 (1H, dd, J=11.7, 4.3 Hz), 3.84 (1H, dd, J=11.7, 8.6 Hz),
3.66 (1H, s), 3.52-3.30 (2H, m), 2.22-2.13 (1H, m), 2.08-2.02 (1H,
m).
(41c) (9S,9aS)-9-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
The title compound (43.0 mg, yield: 66% for 2 steps) was obtained
by production according to the method described in Examples (35c)
and (35d) using 2-chloro-5-nitropyridine-3-carboxylic acid (50 mg,
0.25 mmol) and (2S,3S)-2-(hydroxymethyl)pyrrolidin-3-ol
hydrochloride (38.5 mg, 0.25 mmol) obtained in Example (41b) as
starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.56 (1H, d,
J=3.0 Hz), 9.21 (1H, d, J=3.0 Hz), 5.04 (1H, d, J=13.4 Hz), 4.76
(1H, br s), 4.36 (1H, dd, J=13.4, 7.3 Hz), 4.08-4.04 (2H, m),
3.92-3.89 (1H, m), 2.10-2.07 (2H, m).
(41d) (9S,9aS)-3-amino-9-hydroxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
A crude product of the title compound (28.3 mg, yield: 74%) was
obtained by production according to the method described in Example
(27c) using
(9S,9aS)-9-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (43.0 mg, 0.16 mmol) obtained in
Example (41c) as a starting material.
(41e)
5-chloro-N-[(9S,9aS)-9-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (36.1 mg, yield: 68%) was obtained by production
according to the method described in Example (27d) using
(9S,9aS)-3-amino-9-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (28.3 mg, 0.12 mmol) obtained in
Example (41d) and 5-chloro-2-methoxybenzenesulfonyl chloride (32
mg, 0.13 mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.25 (1H, br s),
8.30 (1H, d, J=3.0 Hz), 8.07 (1H, d, J=3.0 Hz), 7.67-7.63 (2H, m),
7.26 (1H, d, J=9.1 Hz), 5.24 (1H, br s), 4.71 (1H, d, J=12.8 Hz),
4.43 (1H, br s), 4.01 (1H, dd, J=12.8, 7.9 Hz), 3.90 (4H, s),
3.72-3.68 (1H, m), 3.57-3.55 (1H, m), 1.92-1.77 (2H, m).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H)
(Example 42)
5-chloro-N-[(9S,9aS)-9-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de
The title compound (70 mg, yield: 63%) was obtained by production
according to the method described in Example (27d) using
(9S,9aS)-3-amino-9-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (53 mg, 0.23 mmol) obtained in Example
(41d) and 5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride
(73.1 mg, 0.25 mmol) obtained in Example (32a) as starting
materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.75 (1H, br s),
8.26 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 7.89-7.87 (2H, m),
7.64-7.61 (1H, m), 5.25 (1H, d, J=4.3 Hz), 4.75 (1H, d, J=12.9 Hz),
4.46-4.44 (1H, m), 4.05-3.99 (1H, m), 3.91-3.89 (1H, m), 3.73-3.67
(1H, m), 3.59-3.53 (1H, m), 1.95-1.78 (2H, m).
MS spectrum (ES/APCI.sup.+): 494 (M+H), 496 (M+2+H)
(Example 43) Potassium
{[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}[(9S,9aS)-9-hydroxy-5-oxo--
8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]a-
zanide (Potassium Salt of Example 42)
The title compound (49 mg, yield: 84%) was obtained by production
according to the method described in Example 33 using
5-chloro-N-[(9S,9aS)-9-hydroxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de (54 mg, 0.11 mmol) obtained in Example 42 as a starting
material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.84 (1H, d, J=2.7
Hz), 7.78 (1H, d, J=2.7 Hz), 7.73 (1H, d, J=2.7 Hz), 7.50 (1H, dd,
J=9.0, 2.7 Hz), 7.35-7.32 (1H, m), 4.52 (1H, dd, J=12.5, 2.0 Hz),
4.43-4.40 (1H, m), 3.94 (1H, dd, J=12.3, 8.8 Hz), 3.80-3.76 (1H,
m), 3.65-3.62 (1H, m), 3.53-3.51 (1H, m), 1.95-1.76 (2H, m)
(Example 44)
5-chloro-N-[(8S,9aR)-8-fluoro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-
-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
(44a) [(2R,4S)-4-fluoropyrrolidin-2-yl]methanol hydrochloride
A crude product of the title compound (218 mg, yield: 65% for 2
steps) was obtained by production according to the method described
in Examples (35a) and (35b) using
(4S)-1-(tert-butoxycarbonyl)-4-fluoro-D-proline (500 mg, 2.14 mmol)
as a starting material.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 5.45 (1H, dt,
J=52.0, 3.4 Hz), 3.99-3.96 (1H, m), 3.90 (1H, dd, J=11.7, 3.5 Hz),
3.65 (1H, dd, J=11.9, 6.1 Hz), 3.59-3.45 (2H, m), 2.46-2.40 (1H,
m), 2.19-2.02 (1H, m).
(44b) (8S,9aR)-8-fluoro-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
The title compound (144 mg, yield: 28% for 2 steps) was obtained by
production according to the method described in Examples (35c) and
(35d) using 2-chloro-5-nitropyridine-3-carboxylic acid (400 mg,
1.97 mmol) and [(2R,4S)-4-fluoropyrrolidin-2-yl]methanol
hydrochloride (218 mg, 1.4 mmol) obtained in Example (44a) as
starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.53 (1H, d,
J=2.7 Hz), 9.23 (1H, d, J=2.7 Hz), 5.33 (1H, dt, J=51.5, 3.5 Hz),
4.83 (1H, d, J=13.3 Hz), 4.44-4.40 (1H, m), 4.27-4.24 (1H, m),
4.13-4.00 (2H, m), 2.70-2.58 (1H, m), 2.00-1.88 (1H, m).
(44c) (8S,9aR)-3-amino-8-fluoro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
A crude product of the title compound (109 mg, yield: 85%) was
obtained by production according to the method described in Example
(30c) using
(8S,9aR)-8-fluoro-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo-
[2,1-c][1,4]oxazepin-5-one (144 mg, 0.54 mmol) obtained in Example
(44b) as a starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.98 (1H, d,
J=2.7 Hz), 7.89 (1H, d, J=2.7 Hz), 5.27 (1H, dt, J=52.2, 3.3 Hz),
4.61 (1H, dd, J=12.5, 1.2 Hz), 4.32-4.28 (1H, m), 4.10-3.87 (4H,
m), 3.60 (2H, br s), 2.55-2.49 (1H, m), 1.91-1.73 (1H, m).
(44d)
5-chloro-N-[(8S,9aR)-8-fluoro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrid-
o[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (91 mg, yield: 80%) was obtained by production
according to the method described in Example (27d) using
(8S,9aR)-3-amino-8-fluoro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo-
[2,1-c][1,4]oxazepin-5-one (61 mg, 0.26 mmol) obtained in Example
(44c) and 5-chloro-2-methoxybenzenesulfonyl chloride (68.2 mg, 0.26
mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.27 (1H, br s),
8.27 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 7.66-7.64 (2H, m),
7.26 (1H, d, J=8.6 Hz), 5.39-5.26 (1H, m), 4.58 (1H, d, J=11.0 Hz),
4.18-4.12 (2H, m), 3.89 (3H, s), 3.77-3.71 (2H, m), 2.44-2.36 (2H,
m).
MS spectrum (ES/APCI.sup.+): 442 (M+H), 444 (M+2+H).
(Example 45)
5-chloro-N-[(9aR)-8,8-difluoro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
(45a) [(2R)-4,4-difluoropyrrolidin-2-yl]methanol hydrochloride
A crude product of the title compound (332 mg, yield: quantitative
for 2 steps) was obtained by production according to the method
described in Examples (35a) and (35b) using
1-(tert-butoxycarbonyl)-4,4-difluoro-D-proline (500 mg, 1.89 mmol)
as a starting material.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 4.07-4.00 (1H,
m), 3.88 (1H, dd, J=11.7, 3.1 Hz), 3.78-3.68 (3H, m), 2.72-2.61
(1H, m), 2.52-2.38 (1H, m).
(45b) (9aR)-8,8-difluoro-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
The title compound (223 mg, yield: 41% for 2 steps) was obtained by
production according to the method described in Examples (35c) and
(35d) using 2-chloro-5-nitropyridine-3-carboxylic acid (387 mg,
1.91 mmol) and [(2R)-4,4-difluoropyrrolidin-2-yl]methanol
hydrochloride (332 mg, 1.91 mmol) obtained in Example (45a) as
starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.47 (1H, dd,
J=2.7, 1.2 Hz), 9.25 (1H, d, J=2.7 Hz), 4.83-4.77 (1H, m),
4.46-4.34 (2H, m), 4.27-4.22 (1H, m), 4.07-4.03 (1H, m), 2.84-2.74
(1H, m), 2.39-2.25 (1H, m).
(45c) (9aR)-3-amino-8,8-difluoro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
A crude product of the title compound (150 mg, yield: 75%) was
obtained by production according to the method described in Example
(30c) using
(9aR)-8,8-difluoro-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (223 mg, 0.78 mmol) obtained in Example
(45b) as a starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.91 (1H, d,
J=3.1 Hz), 7.86 (1H, d, J=3.1 Hz), 4.57 (1H, dd, J=11.7, 2.0 Hz),
4.32-4.30 (1H, m), 4.23-4.11 (2H, m), 4.05-4.02 (1H, m), 3.66 (2H,
br s), 2.73-2.62 (1H, m), 2.27-2.19 (1H, m).
(45d)
5-chloro-N-[(9aR)-8,8-difluoro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (106 mg, yield: 75%) was obtained by production
according to the method described in Example (27d) using
(9aR)-3-amino-8,8-difluoro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (78 mg, 0.31 mmol) obtained in Example
(45c) and 5-chloro-2-methoxybenzenesulfonyl chloride (81.1 mg, 0.34
mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.34 (1H, br s),
8.20 (1H, d, J=2.7 Hz), 8.12 (1H, d, J=2.7 Hz), 7.68-7.64 (2H, m),
7.27-7.25 (1H, m), 4.57-4.54 (1H, m), 4.28-4.27 (2H, m), 4.12-3.99
(1H, m), 3.90-3.87 (4H, m), 2.49-2.42 (2H, m).
MS spectrum (ES/APCI.sup.+): 460 (M+H), 462 (M+2+H)
(Example 46)
5-chloro-2-methoxy-N-[(8S,9aR)-8-methoxy-5-oxo-8,9,9a,10-tetrahydro-5H,7H-
-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
(46a) (8S,9aR)-8-methoxy-3-nitro-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
To a solution of
(8S,9aR)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (150 mg, 0.57 mmol) obtained in Example
(30b) in N,N-dimethylformamide (5 mL), sodium hydride
(approximately 63% content, 25.9 mg, 0.68 mmol) was added under ice
cooling, and the mixture was stirred at the same temperature as
above for 30 minutes. Subsequently, methyl iodide (0.070 mL, 1.13
mmol) was added thereto under ice cooling, and the mixture was
stirred at room temperature for 18 hours. The mixture was diluted
by addition of water followed by extraction with ethyl acetate. The
organic layer was washed with a saturated aqueous solution of
sodium chloride, and dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (ethyl acetate/methanol=100/0-85/15) to obtain the title
compound (66 mg, yield: 42%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.50 (1H, d,
J=2.7 Hz), 9.21 (1H, d, J=2.7 Hz), 4.78 (1H, d, J=11.7 Hz),
4.30-4.26 (2H, m), 4.04-4.03 (1H, m), 3.95 (1H, br d, J=13.9 Hz),
3.82 (1H, dd, J=13.9, 3.7 Hz), 3.36 (3H, s), 2.46-2.44 (1H, m),
1.80-1.77 (1H, m).
(46b) (8S,9aR)-3-amino-8-methoxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-5-one
The title compound (41 mg, yield: 70%) was obtained by production
according to the method described in Example (30c) using
(8S,9aR)-8-methoxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (66 mg, 0.24 mmol) obtained in Example
(46a) as a starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.96 (1H, d,
J=3.1 Hz), 7.89 (1H, d, J=3.1 Hz), 4.57 (1H, dd, J=12.1, 1.6 Hz),
4.23-4.17 (1H, m), 4.04-3.99 (2H, m), 3.93 (1H, dd, J=13.7, 2.0
Hz), 3.78 (1H, dd, J=13.7, 4.3 Hz), 3.62 (2H, br s), 2.37-2.34 (1H,
m), 1.74-1.70 (1H, m).
(46c)
5-chloro-2-methoxy-N-[(8S,9aR)-8-methoxy-5-oxo-8,9,9a,10-tetrahydro--
5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
The title compound (58 mg, yield: 78%) was obtained by production
according to the method described in Example (27d) using
(8S,9aR)-3-amino-8-methoxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (41 mg, 0.16 mmol) obtained in Example
(46b) and 5-chloro-2-methoxybenzenesulfonyl chloride (43.6 mg, 0.18
mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.27 (1H, br s),
8.23 (1H, d, J=2.7 Hz), 8.09 (1H, d, J=2.7 Hz), 7.67-7.64 (2H, m),
7.26 (1H, d, J=9.0 Hz), 4.52 (1H, br d, J=12.1 Hz), 4.12 (1H, dd,
J=12.1, 8.2 Hz), 4.00-3.94 (2H, m), 3.89 (3H, s), 3.66-3.61 (2H,
m), 2.46-2.44 (1H, m), 2.31-2.25 (1H, m).
MS spectrum (ES/APCI.sup.+): 454 (M+H), 456 (M+2+H)
(Example 47)
(8S,9aR)-3-({[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}amino)-5-oxo-8-
,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8-yl
acetate
(47a)
(8S,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrro-
lo[2,1-c][1,4]oxazepin-8-yl acetate
To a solution of
(8S,9aR)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (200 mg, 0.75 mmol) obtained in Example
(30b) in pyridine (8 mL), acetic anhydride (0.143 mL, 1.51 mmol)
and 4-dimethylaminopyridine (18.4 mg, 0.15 mmol) was added at room
temperature, and the mixture was stirred at the same temperature as
above for 18 hours. The mixture was concentrated under reduced
pressure, and the residue was purified in an automatic
chromatography apparatus (ethyl acetate/methanol=100/0-90/10) to
obtain the title compound (229 mg, yield: 99%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.52 (1H, d,
J=2.7 Hz), 9.23 (1H, d, J=2.7 Hz), 5.41 (1H, t, J=4.3 Hz), 4.80
(1H, d, J=12.1 Hz), 4.37-4.33 (1H, m), 4.27 (1H, dd, J=12.1, 7.8
Hz), 4.05 (1H, dd, J=14.5, 4.3 Hz), 3.90 (1H, dd, J=14.5, 2.0 Hz),
2.48-2.45 (1H, m), 2.07 (3H, s), 1.99-1.96 (1H, m).
(47b)
(8S,9aR)-3-amino-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrro-
lo[2,1-c][1,4]oxazepin-8-yl acetate
The title compound (169 mg, yield: 82%) was obtained by production
according to the method described in Example (30c) using
(8S,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,-
1-c][1,4]oxazepin-8-yl acetate (229 mg, 0.75 mmol) obtained in
Example (47a) as a starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.03 (1H, d,
J=3.1 Hz), 7.94 (1H, d, J=3.1 Hz), 5.40 (1H, t, J=4.3 Hz), 4.63
(1H, dd, J=12.5, 1.2 Hz), 4.30-4.26 (1H, m), 4.08-4.02 (2H, m),
3.91 (1H, br d, J=14.1 Hz), 3.66 (2H, br s), 2.41-2.38 (1H, m),
2.10 (3H, s), 1.95-1.92 (1H, m).
(47c)
(8S,9aR)-3-({[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}amino)-5--
oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8--
yl acetate
The title compound (95 mg, yield: 61%) was obtained by production
according to the method described in Example (27d) using
(8S,9aR)-3-amino-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,-
1-c][1,4]oxazepin-8-yl acetate (80 mg, 0.29 mmol) obtained in
Example (47b) and 5-chloro-2-(trifluoromethoxy)benzenesulfonyl
chloride (102 mg, 0.35 mmol) obtained in Example (32a) as starting
materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.47 (1H, br
s), 8.36 (1H, d, J=2.7 Hz), 7.91 (1H, d, J=2.7 Hz), 7.57 (1H, dd,
J=8.8, 2.5 Hz), 7.36 (1H, br d, J=9.4 Hz), 5.37 (1H, t, J=4.3 Hz),
4.65 (1H, d, J=12.1 Hz), 4.27-4.24 (1H, m), 4.08-4.01 (2H, m), 3.87
(1H, br d, J=14.3 Hz), 2.41-2.36 (1H, m), 2.05 (3H, s), 1.92-1.88
(1H, m).
MS spectrum (ES/APCI.sup.+): 536 (M+H), 538 (M+2+H)
(Example 48)
(8S,9aR)-3-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-8,9,9a,10-te-
trahydro-5H, 7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8-yl
methylcarbamate
(48a)
(8S,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrro-
lo[2,1-c][1,4]oxazepin-8-yl methylcarbamate
To a solution of
(8S,9aR)-8-hydroxy-3-nitro-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-5-one (200 mg, 0.75 mmol) obtained in Example
(30b) in tetrahydrofuran (10 mL), N,N'-carbonyldiimizazole (135 mg,
0.83 mmol) was added at room temperature, and the mixture was
stirred at the same temperature as above for 18 hours.
Subsequently, a 2.0 mol/L solution of methylamine in
tetrahydrofuran (0.829 mL, 2.00 mmol) was added thereto under ice
cooling, and the mixture was stirred at the same temperature as
above for 2 hours. The mixture was diluted by addition of water
followed by extraction with ethyl acetate. The organic layer was
washed with a saturated aqueous solution of sodium chloride, and
dried over anhydrous sodium sulfate. After filtration, the solvent
was distilled off under reduced pressure, and the residue was
purified in an automatic chromatography apparatus (ethyl
acetate/methanol=100/0-95/5) to obtain the title compound (154 mg,
yield: 63%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.51 (1H, br
s), 9.22 (1H, d, J=2.7 Hz), 5.33-3.11 (5H, m), 2.81-2.74 (4H, m),
2.49-1.91 (2H, m).
(48b)
(8S,9aR)-3-amino-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrro-
lo[2,1-c][1,4]oxazepin-8-yl methylcarbamate
A crude product of the title compound (156 mg, yield: quantitative)
was obtained by production according to the method described in
Example (30c) using
(8S,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrr-
olo[2,1-c][1,4]oxazepin-8-yl methylcarbamate (154 mg, 0.48 mmol)
obtained in Example (48a) as a starting material.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 7.84 (1H, d,
J=2.7 Hz), 7.81 (1H, d, J=2.7 Hz), 5.22 (1H, t, J=3.7 Hz), 4.57
(1H, d, J=11.3 Hz), 4.18-4.11 (2H, m), 3.89-3.85 (2H, m), 2.68 (3H,
s), 2.38-2.34 (1H, m), 2.04-1.97 (1H, m).
(48c)
(8S,9aR)-3-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-8,9,9a,-
10-tetrahydro-5H, 7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8-yl
methylcarbamate
The title compound (43 mg, yield: 87%) was obtained by production
according to the method described in Example (27d) using
(8S,9aR)-3-amino-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,-
1-c][1,4]oxazepin-8-yl methylcarbamate (29 mg, 0.10 mmol) obtained
in Example (48b) and 5-chloro-2-methoxybenzenesulfonyl chloride
(28.7 mg, 0.12 mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.26 (1H, br s),
8.23 (1H, d, J=2.9 Hz), 8.10 (1H, d, J=2.9 Hz), 7.67-7.64 (2H, m),
7.26 (1H, d, J=8.8 Hz), 7.06 (1H, br q, J=4.4 Hz), 5.09 (1H, t,
J=3.9 Hz), 4.55 (1H, d, J=12.2 Hz), 4.15 (1H, dd, J=12.2, 7.8 Hz),
4.03-3.98 (1H, m), 3.89 (3H, s), 3.81 (1H, dd, J=13.9, 4.1 Hz),
3.57 (1H, d, J=13.9 Hz), 2.54 (3H, d, J=4.4 Hz), 2.25-2.22 (1H, m),
1.95-1.89 (1H, m).
MS spectrum (ES/APCI.sup.+): 497 (M+H), 499 (M+2+H).
(Example 49) Potassium
[(5-chloro-2-methoxyphenyl)sulfonyl]{(8S,9aR)-8-[(methylcarbamoyl)oxy]-5--
oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3--
yl}azanide (Potassium Salt of Example 48)
The title compound (23 mg, yield: 67%) was obtained by production
according to the method described in Example 33 using
(8S,9aR)-3-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-8,9,9a,10-te-
trahydro-5H, 7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8-yl
methylcarbamate (32.0 mg, 0.064 mmol) obtained in Example (48c) as
a starting material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.76 (1H, d, J=2.9
Hz), 7.71 (1H, d, J=2.9 Hz), 7.64 (1H, d, J=2.9 Hz), 7.32 (1H, dd,
J=9.0, 3.2 Hz), 7.12 (1H, br q, J=4.4 Hz), 6.98 (1H, d, J=8.8 Hz),
5.09 (1H, br s), 4.40 (1H, dd, J=11.7, 2.0 Hz), 4.02-3.90 (2H, m),
3.71-3.67 (5H, m), 2.53 (4H, d, J=4.4 Hz), 2.21-2.19 (1H, m),
1.94-1.89 (1H, m).
(Example 50) methyl
[(8R,9aR)-3-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-8,9,9a,10-t-
etrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8-yl]carbamate (50a)
tert-butyl (2R,4R)-4-{[(benzyloxy)
carbonyl]amino}-2-(hydroxymethyl) pyrrolidine-1-carboxylate
To a solution of 1-tert-butyl 2-methyl
(2R,4R)-4-aminopyrrolidine-1,2-dicarboxylate (2.53 g, 10.4 mmol) in
tetrahydrofuran (50 mL), a saturated aqueous solution of sodium
carbonate (25 mL) was added at room temperature, followed by
addition of benzyl chloroformate (1.77 mL, 12.4 mmol) under ice
cooling, and the mixture was stirred at room temperature for 24
hours. The mixture was diluted by addition of water followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride, and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-50/50) to obtain 1-tert-butyl 2-methyl
(2R,4R)-4-{[(benzyloxy)carbonyl]amino}pyrrolidine-1,2-dicarboxylate
(3.82 g, yield: 98%). To a solution of 1-tert-butyl 2-methyl
(2R,4R)-4-{[(benzyloxy)carbonyl]amino}pyrrolidine-1,2-dicarboxylate
(3.28 g, 10.1 mmol) obtained in the above step in tetrahydrofuran
(100 mL), a 2.0 mol/L solution of lithium borohydride in
tetrahydrofuran (10.1 mL, 20.2 mmol) was added under ice cooling,
and the mixture was stirred at room temperature for 4 days. The
mixture was diluted by addition of water and a saturated aqueous
solution of ammonium chloride under ice cooling followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride, and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
in an automatic chromatography apparatus (n-hexane/ethyl
acetate=100/0-30/70) to obtain the title compound (2.99 g, yield:
85%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.36-7.30 (5H,
m), 5.61-3.56 (9H, m), 3.19 (1H, br s), 2.41 (1H, br s), 1.46 (9H,
s).
(50b) benzyl [(3R,5R)-5-(hydroxymethyl)pyrrolidin-3-yl]carbamate
hydrochloride
A crude product of the title compound (2.45 g, yield: quantitative)
was obtained by production according to the method described in
Example (35b) using tert-butyl
(2R,4R)-4-{[(benzyloxy)carbonyl]amino}-2-(hydroxymethyl)pyrrolidine-1-car-
boxylate (2.99 g, 8.54 mmol) obtained in Example (50a) as a
starting material.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 7.34-7.31 (5H,
m), 5.09 (2H, br s), 4.31-4.30 (1H, m), 3.86-3.83 (1H, m),
3.76-3.70 (2H, m), 3.51-3.48 (1H, m), 3.21-3.18 (1H, m), 2.45-2.42
(1H, m), 1.82-1.78 (1H, m).
(50c) benzyl
[(8R,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2-
,1-c][1,4]oxazepin-8-yl]carbamate
The title compound (2.74 g, yield: 81% for 2 steps) was obtained by
production according to the method described in Examples (35c) and
(35d) using 2-chloro-5-nitropyridine-3-carboxylic acid (1.73 g,
8.54 mmol) and (benzyl
[(3R,5R)-5-(hydroxymethyl)pyrrolidin-3-yl]carbamate hydrochloride
(2.45 g, 8.54 mmol) obtained in Example (50b) as starting
materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.46 (1H, d,
J=2.7 Hz), 9.21 (1H, d, J=3.1 Hz), 7.40-7.33 (5H, m), 5.13 (2H, br
s), 4.94 (1H, br s), 4.74 (1H, d, J=12.5 Hz), 4.34-4.31 (2H, m),
4.16-4.11 (2H, m), 3.63-3.60 (1H, m), 2.68-2.66 (1H, m), 1.79-1.76
(1H, m).
(50d) methyl
[(8R,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2-
,1-c][1,4]oxazepin-8-yl]carbamate
To benzyl
[(8R,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f-
]pyrrolo[2,1-c][1,4]oxazepin-8-yl]carbamate (484 mg, 1.21 mmol)
obtained in Example (50c), a 30% solution of hydrogen bromide in
acetic acid (approximately 5.1 mol/L, 12 mL, 61 mmol) was added
under ice cooling, the mixture was stirred at room temperature for
1 hour. The mixture was concentrated under reduced pressure, the
residue was diluted with methylene chloride (20 mL), triethylamine
(0.505 mL, 3.64 mmol) and methyl chloroformate (0.140 mL, 1.82 mL)
was added thereto under ice cooling, and the mixture was stirred at
room temperature for 20 hours. The mixture was diluted by addition
of water followed by extraction with methylene chloride. The
organic layer was washed with a saturated aqueous solution of
sodium chloride, and dried over anhydrous sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (ethyl acetate/methanol=100/0-90/10) to obtain the title
compound (242 mg, yield: 62%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 9.47 (1H, d,
J=2.7 Hz), 9.22 (1H, d, J=2.7 Hz), 4.77-4.74 (2H, m), 4.33-4.30
(2H, m), 4.17-4.12 (2H, m), 3.72 (3H, s), 3.59-3.53 (1H, m),
2.70-2.64 (1H, m), 1.81-1.73 (1H, m).
(50e) methyl
[(8R,9aR)-3-amino-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2-
,1-c][1,4]oxazepin-8-yl]carbamate
A crude product of the title compound (293 mg, yield: quantitative)
was obtained by production according to the method described in
Example (30c) using methyl
[(8R,9aR)-3-nitro-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2-
,1-c][1,4]oxazepin-8-yl]carbamate (322 mg, 1.00 mmol) obtained in
Example (50d) as a starting material.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 7.80 (1H, d,
J=2.7 Hz), 7.78 (1H, d, J=2.7 Hz), 4.51 (1H, dd, J=11.5, 2.2 Hz),
4.22-4.19 (2H, m), 4.12-4.09 (1H, m), 4.00 (1H, dd, J=12.1, 7.4
Hz), 3.50-3.45 (1H, m), 2.52-2.45 (1H, m), 1.75-1.71 (1H, m).
(50f) methyl
[(8R,9aR)-3-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-8,9,9a,10-t-
etrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8-yl]carbamate
The title compound (80 mg, yield: 94%) was obtained by production
according to the method described in Example (27d) using methyl
[(8R,9aR)-3-amino-5-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2-
,1-c][1,4]oxazepin-8-yl]carbamate (50 mg, 0.17 mmol) obtained in
Example (50e) and 5-chloro-2-methoxybenzenesulfonyl chloride (49.5
mg, 0.21 mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.26 (1H, br s),
8.22 (1H, d, J=2.9 Hz), 8.08 (1H, d, J=2.9 Hz), 7.67-7.62 (2H, m),
7.49 (1H, br d, J=6.8 Hz), 7.26 (1H, d, J=8.8 Hz), 4.51 (1H, d,
J=12.2 Hz), 4.16 (1H, dd, J=12.2, 8.3 Hz), 4.09-3.99 (2H, m), 3.89
(3H, s), 3.76-3.74 (1H, m), 3.55 (4H, br s), 2.39-2.35 (1H, m),
1.58-1.55 (1H, m).
MS spectrum (ES/APCI.sup.+): 497 (M+H), 499 (M+2+H).
(Example 51) Potassium
[(5-chloro-2-methoxyphenyl)sulfonyl]{(8R,9aR)-8-[(methoxycarbonyl)amino]--
5-oxo-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl}azanide (Potassium
Salt of Example 50)
The title compound (59 mg, yield: quantitative) was obtained by
production according to the method described in Example 33 using
methyl
[(8R,9aR)-3-{[(5-chloro-2-methoxyphenyl)sulfonyl]amino}-5-oxo-8,9,9a,10-t-
etrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-8-yl]carbamate (55.0
mg, 0.11 mmol) obtained in Example (50f) as a starting
material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.76 (1H, d, J=2.9
Hz), 7.71 (1H, d, J=2.9 Hz), 7.64 (1H, d, J=2.9 Hz), 7.49 (1H, br
d, J=5.4 Hz), 7.33-7.31 (1H, m), 6.98 (1H, d, J=8.8 Hz), 4.36-4.33
(2H, m), 4.05-4.00 (2H, m), 3.93-3.89 (1H, m), 3.80-3.77 (1H, m),
3.65 (3H, s), 3.54 (3H, br s), 3.45-3.43 (2H, m), 2.34-2.32 (1H,
m), 1.58-1.56 (1H, m).
(Example 52)
5-chloro-2-methoxy-N-[(9aS)-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f-
]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
(52a)
(5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-2-one
To a solution of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (1.00 g,
8.69 mmol) and imidazole (0.710 g, 10.4 mmol) in
N,N-dimethylformamide (15 mL), tert-butyldimethylchlorosilane (1.44
g, 9.55 mmol) was added under ice cooling, and the mixture was
stirred at room temperature for 3 days. The mixture was diluted by
addition of water followed by extraction with ethyl acetate. The
organic layer was washed with water, a 1.0 mol/L hydrochloric acid
and a saturated aqueous solution of sodium chloride, and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure and the residue was purified
in an automatic chromatography apparatus (n-hexane/ethyl
acetate=27/73-6/94) to obtain the title compound (1.66 g, yield:
83%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 5.75 (1H, br
s), 3.79-3.73 (1H, m), 3.63 (1H, dd, J=9.8, 4.0 Hz), 3.44 (1H, dd,
J=9.8, 7.9 Hz), 2.37-2.34 (2H, m), 2.20-2.16 (1H, m), 1.78-1.69
(1H, m), 0.89 (9H, s), 0.06 (6H, s).
(52b) (5-bromo-2-chloropyridin-3-yl)methyl methanesulfonate
To a solution of 5-bromo-2-chloro-pyridine-3-carboxylic acid (6.50
g, 27.5 mmol) and triethylamine (4.19 mL, 30.2 mmol) in
tetrahydrofuran (70 mL), isobutyl chloroformate (3.79 mL, 28.9
mmol) was added under ice cooling, and the mixture was stirred at
the same temperature as above for 1.5 hours. The insoluble matter
was filtered off, and the residue was washed with tetrahydrofuran.
The filtrate and washing were combined, water (14 mL) was added
thereto under ice cooling followed by addition of sodium
borohydride (1.56 g, 41.2 mmol), and the mixture was stirred at the
same temperature as above for 1 hour, and then stirred at room
temperature for 19 hours. The mixture was concentrated under
reduced pressure up to approximately 1/3 volume, diluted by
addition of a 1.0 mol/L hydrochloric acid followed by extraction
with ethyl acetate. The organic layer was washed with water, a
saturated aqueous solution of sodium bicarbonate and a saturated
aqueous solution of sodium chloride, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure to obtain a crude product of
(5-bromo-2-chloropyridin-3-yl)methanol (5.29 g).
To a solution of (5-bromo-2-chloropyridin-3-yl)methanol (5.29 g)
obtained in the above step and triethylamine (8.3 mL, 59.4 mmol) in
methylene chloride (82 mL), methanesulfonyl chloride (3.7 mL, 47.6
mmol) was added under ice cooling, and the mixture was stirred at
the same temperature as above for 1 hour. The mixture was
concentrated under reduced pressure, and the residue was diluted by
addition of water followed by extraction with ethyl acetate. The
organic layer was washed with water and a saturated aqueous
solution of sodium chloride, and dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the residue was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=90/10-65/35) to obtain the title compound
(5.03 g, yield: 61% for 2 steps).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.48 (1H, d,
J=2.4 Hz), 7.98 (1H, d, J=2.4 Hz), 5.29 (2H, s), 3.14 (3H, s).
(52c)
(5S)-1-[(5-bromo-2-chloropyridin-3-yl)methyl]-5-({[tert-butyl(dimeth-
yl)silyl]oxy}methyl)pyrrolidin-2-one
To a suspension of sodium hydride (approximately 63% content, 160
mg, 3.99 mmol) in N,N-dimethylformamide (11 mL), a solution of
(5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-2-one
(840 mg, 3.66 mmol) obtained in Example (52a) in
N,N-dimethylformamide (5.5 mL) was added under ice cooling, and the
mixture was stirred at the same temperature for 20 minutes.
Subsequently, (5-bromo-2-chloropyridin-3-yl)methyl methanesulfonate
(1.00 g, 3.33 mmol) obtained in Example (52b) was added thereto
under ice cooling, the mixture was stirred at the same temperature
as above for 10 minutes, and then stirred at room temperature for
30 minutes. The mixture was poured into ice-water followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of ammonium chloride and a saturated
aqueous solution of sodium chloride, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the residue was purified in an automatic
chromatography apparatus (n-hexane/ethyl acetate=92/8-68/32) to
obtain the title compound (786 mg, yield: 55%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.36 (1H, d,
J=2.4 Hz), 7.73 (1H, d, J=1.8 Hz), 4.74 (1H, d, J=16.5 Hz), 4.45
(1H, d, J=16.5 Hz), 3.74 (1H, dd, J=10.7, 2.7 Hz), 3.70-3.62 (1H,
m), 3.58 (1H, dd, J=10.4, 4.3 Hz), 2.62-2.54 (1H, m), 2.47-2.35
(1H, m), 2.24-2.12 (1H, m), 2.00-1.89 (1H, m), 0.85 (9H, s), 0.01
(6H, s).
(52d)
(9aS)-3-bromo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c]-
[1,4]oxazepin-7-one
To a suspension of
(5S)-1-[(5-bromo-2-chloropyridin-3-yl)methyl]-5-({[tert-butyl(dimethyl)si-
lyl]oxy}methyl)pyrrolidin-2-one (783 mg, 1.80 mmol) in
tetrahydrofuran (30 mL), a 1.0 mol/L solution of
tetra-n-butylammonium fluoride in tetrahydrofuran (3.6 mL, 3.6
mmol) was added at room temperature, and the mixture was stirred at
65-70.degree. C. for 6.5 hours in an oil bath. The mixture was
cooled to room temperature, and diluted by addition of water
followed by extraction with ethyl acetate. The organic layer was
washed with a saturated aqueous solution of sodium chloride, and
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the residue was purified in an
automatic chromatography apparatus (ethyl
acetate/methanol=93/7-68/32) to obtain the title compound (393 mg,
yield: 77%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.24 (1H, d,
J=2.4 Hz), 7.80 (1H, d, J=2.4 Hz), 4.95 (1H, d, J=15.3 Hz), 4.50
(1H, dd, J=12.2, 3.1 Hz), 4.19-4.03 (2H, m), 3.77 (1H, dd, J=12.8,
7.9 Hz), 2.53-2.36 (2H, m), 2.28-2.19 (1H, m), 1.77-1.71 (1H,
m).
(52e)
(9aS)-3-amino-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c]-
[1,4]oxazepin-7-one trifluoroacetate
To a mixture of (9aS)-3-bromo-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-7-one (389 mg, 1.37
mmol) obtained in Example (52d), tert-butyl carbamate (209 mg, 1.79
mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (117
mg, 0.28 mmol) and sodium tert-butoxide (198 mg, 2.06 mmol) in
toluene (120 mL),
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (72 mg,
0.068 mmol) was added at room temperature, the mixture was stirred
under nitrogen atmosphere at the same temperature as above for 1
hour, and then stirred at 80-90.degree. C. for 5.5 hours in an oil
bath. The mixture was cooled to room temperature, and diluted by
addition of ethyl acetate. An insoluble matter was filtered off
through pad of Celite 545.RTM., the filtrate was concentrated under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (methylene chloride/methanol=99/1-91/9) to
obtain tert-butyl
[(9aS)-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]o-
xazepin-3-yl]carbamate (214 mg) as a mixture containing a small
amount of unknown materials.
To a mixture of tert-butyl
[(9aS)-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]o-
xazepin-3-yl]carbamate (214 mg) obtained in the above step in
methylene chloride (3 mL), trifluoroacetic acid (1.5 mL, 20 mmol)
was added at room temperature, and the mixture was stirred at the
same temperature as above for 12 hours. The solvent was distilled
off under reduced pressure, the residue was diluted by addition of
toluene, and the solvent was distilled off under reduced pressure
again. The residue was purified in an automatic chromatography
apparatus (methylene chloride/methanol=99/1-89/11) to obtain the
title compound (86.2 mg, yield: 39% for 2 steps).
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 7.41 (1H, d,
J=3.1 Hz), 6.91 (1H, d, J=2.4 Hz), 5.10 (2H, s), 4.57 (1H, d,
J=15.3 Hz), 4.27 (1H, dd, J=12.8, 3.1 Hz), 4.04-3.95 (2H, m),
3.56-3.42 (1H, m), 2.29-2.20 (2H, m), 2.11-2.02 (1H, m), 1.58-1.45
(1H, m).
(52f)
5-chloro-2-methoxy-N-[(9aS)-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[-
3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]benzenesulfonamide
The title compound (31.8 mg, yield: 31%) was obtained by production
according to the method described in Example (27d) using
(9aS)-3-amino-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]-
oxazepin-7-one trifluoroacetate (80.6 mg, 0.24 mmol) obtained in
Example (52e) and 5-chloro-2-methoxybenzenesulfonyl chloride (71
mg, 0.29 mmol) as starting materials.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 10.28 (1H, br s),
7.78 (1H, d, J=2.4 Hz), 7.72-7.61 (2H, m), 7.45 (1H, d, J=2.4 Hz),
7.25 (1H, d, J=9.2 Hz), 4.68 (1H, d, J=15.9 Hz), 4.41 (1H, dd,
J=12.5, 2.7 Hz), 4.13 (1H, d, J=15.3 Hz), 4.04-3.96 (1H, m), 3.86
(3H, s), 3.74 (1H, dd, J=12.8, 6.7 Hz), 2.36-2.02 (3H, m),
1.68-1.55 (1H, m).
MS spectrum (ES/APCI.sup.+): 424 (M+H), 426 (M+2+H).
(Example 53)
5-chloro-N-[(8R,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
(53a) tert-butyl (2S,4R)-4-hydroxy-2-(hydroxymethyl)
pyrrolidine-1-carboxylate
To a solution of 1-tert-butyl 2-methyl
(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (5.20 g, 21.2 mmol)
in tetrahydrofuran (53 mL), lithium chloride (2.70 g, 63.6 mmol)
and sodium borohydride (2.41 g, 63.6 mmol) at room temperature
followed by addition of ethanol (106 mL), and the mixture was
stirred at the same temperature as above for 24 hours. Water (40
mL) was carefully added thereto, and the mixture was concentrated
under reduced pressure. The residue was diluted by addition of
water (80 mL) followed by extraction with ethyl acetate four times.
The organic layer was washed with a saturated aqueous solution of
sodium chloride, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure to obtain a crude
product of the title compound (5.11 g, yield: quantitative).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.:5.03 (1H, d,
J=6.1 Hz), 4.38 (1H, s), 4.25-4.01 (1H, m), 3.78-3.65 (1H, m),
3.63-3.48 (2H, m), 3.44 (1H, dd, J=12.1, 3.6 Hz), 1.48 (9H, s).
(53b) tert-butyl
(3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl-
]oxy}methyl)-2-oxopyrrolidine-1-carboxylate
To a solution of tert-butyl
(2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (4.61
g, 21.2 mmol) obtained in Example (53a) and imidazole (5.05 g, 74.2
mmol) in N,N-dimethylformamide (45 mL),
tert-butyldimethylchlorosilane (9.59 g, 63.6 mmol) was added under
ice cooling, the mixture was stirred at room temperature for 23.5
hours. The mixture was diluted by addition of n-hexane, ethyl
acetate and a saturated aqueous solution of ammonium chloride,
followed by extraction with ethyl acetate. The organic layer was
washed with a saturated aqueous solution of sodium chloride, and
dried over anhydrous sodium sulfate. After filtration, the solvent
was distilled off under reduced pressure and the residue was
purified in an automatic chromatography apparatus (n-hexane/ethyl
acetate=99/1-95/5) to obtain (tert-butyl
(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl-
]oxy}methyl)pyrrolidine-1-carboxylate) (9.55 g).
To a solution of sodium periodate (11.3 g, 53.0 mmol) in water (140
mL), ruthenium (IV) oxide hydrate (0.480 g, 3.18 mmol) was added at
room temperature, and the mixture was stirred at the same
temperature as above for 10 minutes. The mixture was cooled in an
ice-water bath, then a solution of (tert-butyl
(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl-
]oxy}methyl)pyrrolidine-1-carboxylate) (9.55 g) obtained in the
above step in ethyl acetate (85 mL) was added thereto over 25
minutes period, and the mixture was stirred at room temperature for
15 hours. The mixture was diluted by addition of ethyl acetate, the
insoluble matter was filtered off through pad of Celite 545.RTM.,
and the filtrate was extracted with ethyl acetate. The organic
layer was washed with a saturated aqueous solution of sodium
bicarbonate and a saturated aqueous solution of sodium chloride,
and dried over anhydrous sodium sulfate. After filtration, the
solvent was distilled off under reduced pressure and the residue
was purified in an automatic chromatography apparatus
(n-hexane/ethyl acetate=99/1-88/12) to obtain the title compound
(6.85 g, yield: 70% for 2 steps).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 4.66 (1H, t,
J=9.2 Hz), 4.13 (1H, d, J=9.2 Hz), 3.96 (1H, dd, J=10.4, 2.4 Hz),
3.61 (1H, d, J=10.4 Hz), 2.32 (1H, dd, J=12.2, 8.5 Hz), 2.11-2.00
(1H, m), 1.53 (9H, s), 0.91 (9H, s), 0.87 (9H, s), 0.16 (3H, s),
0.12 (3H, s), 0.04 (3H, s), 0.01 (3H, s).
(53c)
(3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)-
silyl]oxy}methyl)pyrrolidin-2-one
To a solution of tert-butyl
(3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl-
]oxy}methyl)-2-oxopyrrolidine-1-carboxylate (6.85 g, 14.9 mmol)
obtained in Example (53b) in methylene chloride (150 mL),
trifluoroacetic acid (11.4 mL, 149 mmol) was added at room
temperature, and the mixture was stirred at the same temperature as
above for 30 minutes. The mixture was cooled in an ice-water bath,
diluted by addition of a saturated aqueous solution of sodium
bicarbonate (180 mL) followed by extraction with methylene
chloride. The organic layer was washed with a saturated aqueous
solution of sodium chloride, and dried over anhydrous sodium
sulfate. After filtration, the solvent was distilled off under
reduced pressure and the residue was purified in an automatic
chromatography apparatus (n-hexane/ethyl acetate=95/5-65/35) to
obtain the title compound (5.28 g, yield: 99%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 4.35 (1H, t,
J=7.0 Hz), 5.71 (1H, br s), 3.79-3.69 (1H, m), 3.60 (1H, dd,
J=10.4, 3.7 Hz), 3.44 (1H, dd, J=10.1, 6.4 Hz), 2.09 (2H, t, J=6.4
Hz), 0.91 (9H, s), 0.89 (9H, s), 0.16 (3H, s), 0.14 (3H, s), 0.06
(3H, s), 0.05 (3H, s).
(53d)
(3R,5S)-1-[(5-bromo-2-chloropyridin-3-yl)methyl]-3-hydroxy-5-(hydrox-
ymethyl)pyrrolidin-2-one
To a suspension of sodium hydride (approximately 63% content, 56
mg, 1.42 mmol) in tetrahydrofuran (5 mL), a solution of
(3R,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl-
]oxy}methyl)pyrrolidin-2-one (500 mg, 1.39 mmol) obtained in
Example (53c) was added at room temperature, and the mixture was
stirred at the same temperature for 30 minutes. Subsequently, a
solution of (5-bromo-2-chloropyridin-3-yl)methyl methanesulfonate
(422 mg, 1.40 mmol) obtained in Example (52b) in teterahydrofuran
(2.5 mL) was added thereto, the mixture was stirred under reflux
for 1.5 hours. After cooling, the mixture was poured into a mixture
of ice and a saturated aqueous solution of ammonium chloride
followed by extraction with ethyl acetate. The organic layer was
washed with a saturated aqueous solution of sodium chloride, and
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the residue was purified in an
automatic chromatography apparatus (n-hexane/ethyl
acetate=99/1-78/22) to obtain
((3R,5S)-1-[(5-bromo-2-chloropyridin-3-yl)methyl]-3-{[tert-butyl(d-
imethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-2--
one) (753 mg yield: 96%).
To a solution of
((3R,5S)-1-[(5-bromo-2-chloropyridin-3-yl)methyl]-3-{[tert-butyl(dimethyl-
)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-2-one)
(751 mg, 1.33 mmol) obtained in the above step in tetrahydrofuran
(22 mL), a 1.0 mol/L solution of tetra-n-butylammonium fluoride in
tetrahydrofuran (3.3 mL, 3.3 mmol) was added at room temperature,
and the mixture was stirred at the same temperature as above for 20
minutes. The mixture was diluted by addition of a saturated aqueous
solution of ammonium chloride followed by extraction with ethyl
acetate twice. The organic layer was washed with a saturated
aqueous solution of sodium chloride, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the residue was purified in an automatic
chromatography apparatus (ethyl acetate/methanol=99/1-89/11) to
obtain the title compound (331 mg, yield: 74%).
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 8.51 (1H, d,
J=2.4 Hz), 7.85 (1H, d, J=2.4 Hz), 5.74-5.45 (1H, m), 4.96 (1H, br
s), 4.59 (1H, d, J=16.5 Hz), 4.37-4.28 (2H, m), 3.61-3.51 (2H, m),
3.42-3.36 (1H, m), 2.22 (1H, ddd, J=12.8, 8.2, 1.8 Hz), 1.97-1.85
(1H, m)
(53e) (8R,9aS)-3-bromo-8-hydroxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-7-one
To a solution of
(3R,5S)-1-[(5-bromo-2-chloropyridin-3-yl)methyl]-3-hydroxy-5-(hydroxymeth-
yl)pyrrolidin-2-one (335 mg, 1.00 mmol) obtained in Example (53d)
in N,N-dimethylformamide (20 mL), potassium carbonate (414 mg, 2.99
mmol) was added at room temperature, and the mixture was stirred at
120-125.degree. C. for 4 hours in an oil bath. After cooling, the
mixture was poured into a mixture of ethyl acetate and a saturated
aqueous solution of ammonium chloride followed by extraction with a
mixed solvent of methylene chloride/isopropanol=3/1 three times.
The organic layer was dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, isopropanol was
added to the residue, and the suspension was stirred at room
temperature for a while. The precipitated solid was collected by
filtration to obtain the title compound (284 mg, yield: 95%).
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 8.23 (1H, d,
J=2.4 Hz), 8.11 (1H, d, J=2.4 Hz), 5.73 (1H, br s), 4.81 (1H, d,
J=15.9 Hz), 4.48 (1H, dd, J=12.8, 3.1 Hz), 4.26 (1H, d, J=15.9 Hz),
4.16-4.05 (2H, m), 3.84 (1H, dd, J=12.5, 7.0 Hz), 2.04-1.87 (2H, m)
(53f) 5-chloro-2-methoxybenzenesulfonamide
To a solution of 5-chloro-2-methoxybenzenesulfonyl chloride (3 g,
12.4 mmol) in tetrahydrofuran (20 mL), a 28% aqueous ammonia
solution (20 mL, 295 mmol) was added, and the mixture was stirred
at room temperature for 19 hours. The reaction mixture was diluted
by addition of 1 mol/L hydrochloric acid, followed by extraction
with ethyl acetate. The organic layer was washed with water and a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure to obtain the title compound
(2.74 g, yield: quantitative).
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 7.91 (1H, d, J=3.0
Hz), 7.56-7.46 (1H, m), 7.00 (1H, d, J=8.5 Hz), 5.06 (2H, br s),
4.02 (3H, s).
(53g)
5-chloro-N-[(8R,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
To a mixture of
(8R,9aS)-3-bromo-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-7-one (120 mg, 0.40 mmol) obtained in Example
(53e), 5-chloro-2-methoxybenzenesulfonamide (116 mg, 0.52 mmol)
obtained in Example (53f), N,N-dimethylglycine (20.7 mg, 0.20 mmol)
and tripotassium phosphate (255 mg, 1.20 mmol) in dimethylsulfoxide
(1.2 mL), copper (I) iodide (31 mg, 0.12 mmol) was added at room
temperature, and the mixture was stirred under nitrogen atmosphere
at 120-125.degree. C. for 3.5 hours in an oil bath. After cooling,
the mixture was diluted by addition of a saturated aqueous solution
of ammonium chloride, and the insoluble matter was filtered off.
The filtrate was diluted by addition of a 2.0 mol/L hydrochloric
acid (5 mL) and a saturated aqueous solution of sodium chloride
followed by extraction with a mixed solvent of methylene
chloride/isopropanol=3/1. The organic layer was dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the residue was purified in an automatic
chromatography apparatus (methylene chloride/methanol=98/2-91/9) to
obtain a solid. To the solid, isopropanol was added, and the
suspension was stirred at room temperature for a while. The
precipitated solid was collected by filtration to obtain the title
compound (57.3 mg, yield: 33%).
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.31 (1H, br
s), 7.79 (1H, d, J=2.4 Hz), 7.71-7.65 (2H, m), 7.47 (1H, d, J=3.1
Hz), 7.24 (1H, d, J=8.5 Hz), 5.69 (1H, d, J=4.9 Hz), 4.67 (1H, d,
J=15.3 Hz), 4.38 (1H, dd, J=12.8, 3.1 Hz), 4.17 (1H, d, J=15.3 Hz),
4.09-4.00 (2H, m), 3.85 (3H, s), 3.68 (1H, dd, J=12.8, 7.9 Hz),
1.98-1.84 (2H, m).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H)
(Example 54)
5-chloro-N-[(8S,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
(54a) tert-butyl (2S,4S)-4-hydroxy-2-(hydroxymethyl)
pyrrolidine-1-carboxylate
The title compound (8.02 g, yield: quantitative) was obtained by
production according to the method described in Example (53a) using
(4S)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (9.00 g, 36.7
mmol) as a starting material.
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 4.31 (1H, br s),
4.07-4.00 (3H, m), 3.60-3.44 (4H, m), 2.36-2.32 (1H, m), 1.94-1.83
(1H, m), 1.47 (9H, s).
(54b) tert-butyl
(3S,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl-
]oxy}methyl)-2-oxopyrrolidine-1-carboxylate
The title compound (4.73 g, yield: 63% for 2 steps) was obtained by
production according to the method described in Example (53b) using
tert-butyl
(2S,4S)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.6
g, 17 mmol) obtained in Example (54a) as a starting material.
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 4.24 (1H, dd, J=8.2,
5.5 Hz), 4.03-3.99 (1H, m), 3.85-3.80 (2H, m), 2.25-2.21 (1H, m),
2.06-2.00 (1H, m), 1.53 (9H, s), 0.90 (9H, s), 0.88 (9H, s), 0.15
(3H, s), 0.13 (3H, s), 0.05 (3H, s), 0.04 (3H, s).
(54c)
(3S,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)-
silyl]oxy}methyl)pyrrolidin-2-one
The title compound (2.32 g, yield: 63%) was obtained by production
according to the method described in Example (53c) using tert-butyl
(3S,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl-
]oxy}methyl)-2-oxopyrrolidine-1-carboxylate (4.73 g, 10.3 mmol)
obtained in Example (54b) as a starting material.
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 5.85 (1H, br s),
4.30 (1H, t, J=7.8 Hz), 3.68-3.43 (3H, m), 2.43-2.39 (1H, m),
1.59-1.56 (2H, m), 0.91 (9H, s), 0.89 (9H, s), 0.17 (3H, s), 0.14
(3H, s), 0.06 (6H, s).
(54d) (8S,9aS)-3-bromo-8-hydroxy-8,9,9a,10-tetrahydro-5H,
7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-7-one
The title compound (734 mg, yield: 45% for 3 steps) was obtained by
production according to the method described in Examples (53d) and
(53e) using
(3S,5S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl-
)silyl]oxy}methyl)pyrrolidin-2-one (1.976 g, 5.51 mmol) obtained in
Example (54c) and (5-bromo-2-chloropyridin-3-yl)methyl
methanesulfonate (1.74 g, 5.78 mmol) obtained in Example (52b) as
starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 8.20 (1H, d,
J=2.4 Hz), 8.10 (1H, d, J=2.4 Hz), 4.80 (1H, d, J=16.4 Hz), 4.62
(1H, dd, J=13.4, 3.0 Hz), 4.33 (1H, d, J=15.8 Hz), 4.24 (1H, t,
J=8.8 Hz), 3.99 (1H, dd, J=13.1, 3.9 Hz), 3.92-3.83 (1H, m),
2.48-2.38 (1H, m), 1.64-1.54 (1H, m).
(54e)
5-chloro-N-[(8S,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
The title compound (550 mg, yield: 43%) was obtained by production
according to the method described in Example (53g) using
(8S,9aS)-3-bromo-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-7-one (870 mg, 2.91 mmol) obtained in Example
(54d) and 5-chloro-2-methoxybenzenesulfonamide (838 mg, 3.78 mmol)
obtained in Example (53f) as starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.25 (1H, br
s), 7.76 (1H, d, J=2.4 Hz), 7.71-7.64 (2H, m), 7.47 (1H, d, J=2.4
Hz), 7.25 (1H, dd, J=7.3, 2.4 Hz), 5.57 (1H, d, J=6.1 Hz), 4.68
(1H, d, J=15.8 Hz), 4.51 (1H, dd, J=14.6, 4.3 Hz), 4.28-4.16 (2H,
m), 3.89-3.79 (5H, m), 2.44-2.35 (1H, m), 1.56-1.46 (1H, m).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H).
(Example 55) Potassium
[(5-chloro-2-methoxyphenyl)sulfonyl][(8S,9aS)-8-hydroxy-7-oxo-8,9,9a,10-t-
etrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]azanide
(Potassium Salt of Example 54)
The title compound (23.2 mg, yield: 95%) was obtained by production
according to the method described in Example 33 using
5-chloro-N-[(8S,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-methoxybenzenesulfonamide
(22.4 mg, 0.051 mmol) obtained in Example (54e) as a starting
material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.65 (1H, d, J=3.1
Hz), 7.41 (1H, d, J=2.4 Hz), 7.33 (1H, dd, J=8.9, 2.7 Hz), 7.18
(1H, d, J=3.1 Hz), 6.98 (1H, d, J=9.2 Hz), 5.57 (1H, br s), 4.51
(1H, d, J=15.3 Hz), 4.31 (1H, dd, J=12.8, 3.1 Hz), 4.15 (1H, t,
J=8.2 Hz), 4.07-3.98 (1H, m), 3.84-3.74 (1H, m), 3.65 (3H, s), 3.53
(1H, dd, J=12.5, 7.0 Hz), 2.43-2.32 (1H, m), 1.41-1.30 (1H, m).
(Example 56)
5-chloro-N-[(8S,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de
(56a) 5-chloro-2-(trifluoromethoxy)benzenesulfonamide
The title compound (2.44 g, yield: 74%) was obtained by production
according to the method described in Example (53f) using
5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride (3.52 g, 11.9
mmol) obtained in Example (32a) as a starting material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.92 (1H, d, J=2.4
Hz), 7.89-7.80 (3H, m), 7.62 (1H, dd, J=8.8, 1.5 Hz).
(56b)
5-chloro-N-[(8S,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyri-
do[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulf-
onamide
The title compound (28 mg, yield: 11%) was obtained by production
according to the method described in Example (53g) using
(8S,9aS)-3-bromo-8-hydroxy-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrol-
o[2,1-c][1,4]oxazepin-7-one (150 mg, 0.50 mmol) obtained in Example
(54d) and 5-chloro-2-(trifluoromethoxy)benzenesulfonamide (838 mg,
3.78 mmol) obtained in Example (56a) as starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.75 (1H, br
s), 7.93 (1H, d, J=2.3 Hz), 7.85 (1H, dd, J=8.6, 2.3 Hz), 7.75 (1H,
d, J=2.3 Hz), 7.61 (1H, d, J=9.4 Hz), 7.48 (1H, d, J=2.3 Hz), 5.58
(1H, d, J=6.3 Hz), 4.70 (1H, d, J=16.0 Hz), 4.52-4.49 (1H, m),
4.24-4.18 (2H, m), 3.85-3.83 (2H, m), 2.44-2.37 (1H, m), 1.52-1.49
(1H, m).
MS spectrum (ES/APCI.sup.+): 494 (M+H), 496 (M+2+H).
(Example 57) Potassium
{[5-chloro-2-(trifluoromethoxy)phenyl]sulfonyl}[(8S,9aS)-8-hydroxy-7-oxo--
8,9,9a,10-tetrahydro-5H,7H-pyrido[3,2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]a-
zanide (Potassium Salt of Example 56)
The title compound (23 mg, yield: 97%) was obtained by production
according to the method described in Example 33 using
5-chloro-N-[(8S,9aS)-8-hydroxy-7-oxo-8,9,9a,10-tetrahydro-5H,7H-pyrido[3,-
2-f]pyrrolo[2,1-c][1,4]oxazepin-3-yl]-2-(trifluoromethoxy)benzenesulfonami-
de (22 mg, 0.045 mmol) obtained in Example (56b) as a starting
material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.79 (1H, d, J=2.7
Hz), 7.51 (1H, dd, J=8.6, 2.7 Hz), 7.45 (1H, d, J=2.7 Hz), 7.34
(1H, d, J=8.6 Hz), 7.15 (1H, d, J=2.7 Hz), 4.52 (1H, d, J=14.9 Hz),
4.33-4.31 (1H, m), 4.16-4.14 (1H, m), 4.03 (1H, d, J=14.9 Hz),
3.80-3.77 (1H, m), 3.56 (1H, dd, J=12.7, 6.8 Hz), 2.40-2.33 (1H,
m), 1.40-1.33 (1H, m).
(Example 58) 5-chloro-2-methoxy-N-[(9aR)-7-oxo-9a,10-dihydro-5H,
9H-[1,3]oxazolo[4,3-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide
(58a)
(4S)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-oxazolidin-2-one
The title compound (426 mg, yield: 79%) was obtained by production
according to the method described in Example (52a) using
(4R)-4-(hydroxymethyl)-1,3-oxazolidin-2-one (272 mg, 2.32 mmol) as
a starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 5.19 (1H, br
s), 4.46 (1H, t, J=8.5 Hz), 4.14 (1H, dd, J=9.1, 4.9 Hz), 3.97-3.91
(1H, m), 3.66-3.58 (2H, m), 0.89 (9H, s), 0.07 (6H, s).
(58b)
(9aR)-3-bromo-9a,10-dihydro-5H,9H-[1,3]oxazolo[4,3-c]pyrido[3,2-f][1-
,4]oxazepin-7-one
The title compound (248 mg, yield: 49% for 3 steps) was obtained by
production according to the method described in Examples (53d) and
(53e) using
(4S)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-oxazolidin-2-on-
e (428 mg, 1.85 mmol) obtained in Example (58a) and
(5-bromo-2-chloropyridin-3-yl)methyl methanesulfonate (530 mg, 1.76
mmol) obtained in Example (52b) as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.28 (1H, d,
J=2.4 Hz), 7.80 (1H, d, J=2.4 Hz), 4.71 (1H, d, J=15.8 Hz),
4.54-4.45 (2H, m), 4.38-4.27 (2H, m), 4.02 (1H, dd, J=9.1, 5.5 Hz),
3.90 (1H, dd, J=12.8, 8.5 Hz).
(58c) (9aR)-3-amino-9a, 10-dihydro-5H,
9H-[1,3]oxazolo[4,3-c]pyrido[3,2-f][1,4]oxazepin-7-one
The title compound (43.3 mg, yield: 23% for 2 steps) was obtained
by production according to the method described in Example (52e)
using (9aR)-3-bromo-9a,10-dihydro-5H,
9H-[1,3]oxazolo[4,3-c]pyrido[3,2-f][1,4]oxazepin-7-one (246 mg,
0.86 mmol) obtained in Example (58b) as a starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.65 (1H, d,
J=3.1 Hz), 7.01 (1H, d, J=3.1 Hz), 4.60 (1H, d, J=15.3 Hz),
4.47-4.38 (2H, m), 4.34-4.24 (2H, m), 3.92 (1H, dd, J=9.2, 5.5 Hz),
3.76 (1H, dd, J=12.5, 9.5 Hz), 3.65-3.57 (2H, m).
(58d) 5-chloro-2-methoxy-N-[(9aR)-7-oxo-9a,10-dihydro-5H,
9H-[1,3]oxazolo[4,3-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide
The title compound (76.2 mg, yield: 93%) was obtained by production
according to the method described in Example (27d) using
(9aR)-3-amino-9a,10-dihydro-5H,9H-[1,3]oxazolo[4,3-c]pyrido[3,2-f][1,4]ox-
azepin-7-one (42.8 mg, 0.19 mmol) obtained in Example (58c) and
5-chloro-2-methoxybenzenesulfonyl chloride (51 mg, 0.21 mmol) as
starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.29 (1H, br
s), 7.78 (1H, d, J=2.4 Hz), 7.70-7.65 (2H, m), 7.48 (1H, d, J=3.1
Hz), 7.28-7.21 (1H, m), 4.53-4.38 (4H, m), 4.28-4.18 (1H, m), 4.04
(1H, dd, J=9.2, 5.5 Hz) 3.94 (1H, dd, J=13.1, 5.2 Hz), 3.84 (3H,
s).
MS spectrum (ES/APCI.sup.+): 426 (M+H), 428 (M+2+H).
(Example 59) 5-chloro-2-methoxy-N-[(10aS)-7-oxo-7,8,9,10,10a,
11-hexahydro-5H-dipyrido[2,1-c:3',2'-f][1,4]oxazepin-3-yl]benzenesulfonam-
ide
(59a)
(6S)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidin-2-one
The title compound (318 mg, yield: 40%) was obtained by production
according to the method described in Example (52a) using
(6S)-6-(hydroxymethyl)piperidin-2-one (421 mg, 3.26 mmol) as a
starting material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 6.12 (1H, br
s), 3.63 (1H, dd, J=9.4, 3.3 Hz), 3.53-3.43 (1H, m), 3.37 (1H, t,
J=9.4 Hz), 2.49-2.36 (1H, m), 2.35-2.22 (1H, m), 1.94-1.87 (1H, m),
1.86-1.77 (1H, m), 1.76-1.66 (1H, m), 1.33-1.23 (1H, m), 0.89 (9H,
s), 0.06 (6H, s).
(59b)
(10aS)-3-bromo-9,10,10a,11-tetrahydro-5H-dipyrido[2,1-c:3',2'-f][1,4-
]oxazepin-7(8H)-one
The title compound (178 mg, yield: 60% for 2 steps) was obtained by
production according to the method described in Examples (52c) and
(52d) using
(6S)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)piperidin-2-one (260
mg, 1.05 mmol) obtained in Example (59a) and
(5-bromo-2-chloropyridin-3-yl)methyl methanesulfonate (300 mg, 1.00
mmol) obtained in Example (52b) as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.19 (1H, d,
J=2.4 Hz), 7.82 (1H, d, J=2.4 Hz), 5.33 (1H, d, J=14.6 Hz), 4.50
(1H, dd, J=15.3, 5.5 Hz), 4.03-3.93 (3H, m), 2.53-2.43 (1H, m),
2.36-2.28 (1H, m), 2.08-1.98 (1H, m), 1.90-1.73 (3H, m).
(59c)
5-chloro-2-methoxy-N-[(10aS)-7-oxo-7,8,9,10,10a,11-hexahydro-5H-dipy-
rido[2,1-c:3',2'-f][1,4]oxazepin-3-yl]benzenesulfonamide
The title compound (7.5 mg, yield: 3% for 3 steps) was obtained by
production according to the method described in Examples (52e) and
(27d) using
(10aS)-3-bromo-9,10,10a,11-tetrahydro-5H-dipyrido[2,1-c:3',2'-f][1,-
4]oxazepin-7(8H)-one (178 mg, 0.60 mmol) obtained in Example (59b)
and 5-chloro-2-methoxybenzenesulfonyl chloride (45 mg, 0.19 mmol)
as starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.19 (1H, br
s), 7.73 (1H, d, J=2.4 Hz), 7.67-7.66 (2H, m), 7.40 (1H, d, J=2.4
Hz), 7.24 (1H, d, J=9.8 Hz), 5.00 (1H, d, J=15.3 Hz), 4.51 (1H, dd,
J=12.8, 2.4 Hz), 4.15 (1H, d, J=15.3 Hz), 3.92-3.87 (5H, m),
2.33-2.12 (2H, m), 1.92 (1H, s), 1.71-1.66 (3H, m).
MS spectrum (ES/APCI.sup.+): 438 (M+H), 440 (M+2+H)
(Example 60)
5-chloro-2-methoxy-N-[(10aS)-7-oxo-7,8,10a,11-tetrahydro-5H,10H-[1,4]oxaz-
ino[3,4-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide
(60a) tert-butyl
(3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxomorpholine-4-carboxy-
late
The title compound (753 mg, yield: 56% for 3 steps) was obtained by
production according to the method described in Examples (53a) and
(53b) using 4-tert-butyl 3-methyl
(3S)-5-oxomorpholine-3,4-dicarboxylate (1.67 g, 6.81 mmol) as a
starting material.
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 4.29-4.10 (3H, m),
4.10-4.04 (1H, m), 3.79 (1H, t, J=9.1 Hz), 3.73-3.65 (2H, m), 1.55
(9H, s), 0.89 (9H, s), 0.08 (6H, s)
(60b)
(5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-3-one
The title compound (371 mg, yield: 70%) was obtained by production
according to the method described in Example (53c) using tert-butyl
(3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxomorpholine-4-carboxy-
late (750 mg, 2.17 mmol) obtained in Example (60a) as a starting
material.
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 6.23 (1H, br s),
4.24-4.08 (2H, m), 3.88-3.83 (1H, m), 3.70-3.52 (4H, m), 0.90 (9H,
s), 0.08 (6H, s).
(60c)
(10aS)-3-bromo-10a,11-dihydro-5H,10H-[1,4]oxazino[3,4-c]pyrido[3,2-f-
][1,4]oxazepin-7(8H)-one
The title compound (117 mg, yield: 50% for 3 steps) was obtained by
production according to the method described in Examples (53d) and
(53e) using
(5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholin-3-one (190
mg, 0.77 mmol) obtained in Example (60b) and
(5-bromo-2-chloropyridin-3-yl)methyl methanesulfonate (256 mg, 0.85
mmol) obtained in Example (52b) as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.19 (1H, d,
J=2.4 Hz), 8.07 (1H, d, J=2.4 Hz), 5.12 (1H, d, J=15.8 Hz), 4.67
(1H, dd, J=14.0, 4.3 Hz), 4.38 (1H, d, J=15.8 Hz), 4.17-3.98 (5H,
m), 3.79-3.70 (1H, m).
(60d)
5-chloro-2-methoxy-N-[(10aS)-7-oxo-7,8,10a,11-tetrahydro-5H,10H-[1,4-
]oxazino[3,4-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide
The title compound (68.6 mg, yield: 41%) was obtained by production
according to the method described in Example (53g) using
5-chloro-2-methoxy-N-[(10aS)-7-oxo-7,8,10a,11-tetrahydro-5H,10H-[1,4]oxaz-
ino[3,4-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide (115
mg, 0.38 mmol) obtained in Example (60c) and
5-chloro-2-methoxybenzenesulfonamide (119 mg, 0.54 mmol) obtained
in Example (53f) as starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.24 (1H, br
s), 7.75 (1H, d, J=3.0 Hz), 7.69-7.64 (2H, m), 7.44 (1H, d, J=3.0
Hz), 7.27-7.21 (1H, m), 5.00 (1H, d, J=15.8 Hz), 4.56 (1H, dd,
J=13.1, 2.7 Hz), 4.27 (1H, d, J=15.2 Hz), 4.11-3.93 (5H, m), 3.86
(3H, s), 3.71 (1H, dd, J=13.1, 8.8 Hz).
MS spectrum (ES/APCI.sup.+): 440 (M+H), 442 (M+2+H)
(Example 61)
2-ethoxy-5-fluoro-N-[(10aS)-7-oxo-7,8,10a,11-tetrahydro-5H,10H-[1,4]oxazi-
no[3,4-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide
(61a)
(10aS)-3-amino-10a,11-dihydro-5H,10H-[1,4]oxazino[3,4-c]pyrido[3,2-f-
][1,4]oxazepin-7 (8H)-one
The title compound (114.5 mg, yield: 69% for 2 steps) was obtained
by production according to the method described in Example (52e)
using (10aS)-3-bromo-10a,
11-dihydro-5H,10H-[1,4]oxazino[3,4-c]pyrido[3,2-f][1,4]oxazepin-7(8H)-one
(210 mg, 0.70 mmol) obtained in Example (60c) as a starting
material.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.63 (1H, d,
J=3.0 Hz), 7.07 (1H, d, J=3.0 Hz), 5.23 (1H, d, J=14.6 Hz), 4.42
(1H, dd, J=12.1, 2.4 Hz), 4.21-4.08 (2H, m), 4.06-3.92 (4H, m),
3.86 (1H, dd, J=11.5, 3.6 Hz), 3.58 (2H, br s).
(61b) 5-fluoro-2-ethoxybenzenesulfonyl chloride
To chlorosulfonic acid (30.0 mL, 451 mmol),
1-ethoxy-4-fluorobenzene (10.33 mL, 73.7 mmol) was added at
-12.degree. C. over 10 minutes, the mixture was stirred at the same
temperature as above for 30 minutes, and subsequently stirred in an
ice water bath for 1 hour. The reaction mixture was carefully
poured into ice water (approximately 300 mL), followed by
extraction with ethyl acetate. The organic layer was washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous magnesium sulfate. After filtration, the solvent was
distilled off under reduced pressure, and the residue was purified
by silica gel column chromatography (n-hexane/ethyl acetate=4/1).
To the obtained solid, n-hexane was added, and the suspension was
cooled in ice water bath. The precipitated solid was collected by
filtration, washed with n-hexane, and then dried to obtain the
title compound (7.69 g, yield: 44%).
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 7.70 (1H, dd,
J=7.4, 3.1 Hz), 7.41-7.36 (1H, m), 7.07 (1H, dd, J=9.4, 3.9 Hz),
4.26 (2H, q, J=6.8 Hz), 1.55 (3H, t, J=6.8 Hz).
(61c)
2-ethoxy-5-fluoro-N-[(10aS)-7-oxo-7,8,10a,11-tetrahydro-5H,10H-[1,4]-
oxazino[3,4-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide
The title compound (50.9 mg, yield: 66%) was obtained by production
according to the method described in Example (27d) using
(10aS)-3-amino-10a,11-dihydro-5H,
10H-[1,4]oxazino[3,4-c]pyrido[3,2-f][1,4]oxazepin-7(8H)-one (41.5
mg, 0.18 mmol) obtained in Example (61a) and
5-fluoro-2-ethoxybenzenesulfonyl chloride (48.3 mg, 0.19 mmol)
obtained in Example (61b) as starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.11 (1H, br
s), 7.77 (1H, d, J=2.4 Hz), 7.54 (1H, dd, J=7.9, 3.0 Hz), 7.50-7.41
(2H, m), 7.23 (1H, dd, J=9.1, 4.3 Hz), 4.99 (1H, d, J=15.8 Hz),
4.54 (1H, dd, J=13.4, 3.0 Hz), 4.25 (1H, d, J=15.8 Hz), 4.14 (2H,
q, J=6.9 Hz), 4.10-3.98 (4H, m), 3.97-3.93 (1H, m), 3.72 (1H, dd,
J=12.8, 8.5 Hz), 1.22 (3H, t, J=7.0 Hz).
MS spectrum (ES/APCI.sup.+): 438 (M+H).
(Example 62) Potassium
[(2-ethoxy-5-fluorophenyl)sulfonyl][(10aS)-7-oxo-7,8,10a,11-tetrahydro-5H-
,10H-[1,4]oxazino[3,4-c]pyrido[3,2-f][1,4]oxazepin-3-yl]azanide
(Potassium Salt of Example 61)
The title compound (32.1 mg, yield: 99%) was obtained by production
according to the method described in Example 33 using
2-ethoxy-5-fluoro-N-[(10aS)-7-oxo-7,8,10a,11-tetrahydro-5H,10H-[1,4]oxazi-
no[3,4-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide (29.8
mg, 0.068 mmol) obtained in Example (61c) as a starting
material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.45-7.40 (2H, m),
7.19 (1H, d, J=3.0 Hz), 7.08 (1H, td, J=8.5, 3.2 Hz), 6.94 (1H, dd,
J=9.1, 4.3 Hz), 4.90 (1H, d, J=14.6 Hz), 4.33 (1H, dd, J=12.5, 2.1
Hz), 4.08-3.86 (7H, m), 3.78-3.71 (2H, m), 1.09 (3H, t, J=7.0
Hz).
Example 63
The title compound (38.0 mg, yield: 52%) was obtained by production
according to the method described in Example (27d) using
(10aS)-3-amino-10a,11-dihydro-5H,
10H-[1,4]oxazino[3,4-c]pyrido[3,2-f][1,4]oxazepin-7(8H)-one (35.1
mg, 0.15 mmol) obtained in Example (61a) and
5-chloro-2-(trifluoromethoxy)benzenesulfonyl chloride (49.5 mg,
0.16 mmol) obtained in Example (32a) as starting materials.
.sup.1H NMR spectrum (DMSO-d.sub.6, 400 MHz) .delta.: 10.72 (1H, br
s), 7.91 (1H, d, J=2.4 Hz), 7.87 (1H, dd, J=8.5, 2.4 Hz), 7.77 (1H,
d, J=2.4 Hz), 7.61 (1H, dd, J=8.8, 1.5 Hz), 7.46 (1H, d, J=3.0 Hz),
5.03 (1H, d, J=15.2 Hz), 4.56 (1H, dd, J=13.4, 2.4 Hz), 4.25 (1H,
d, J=15.2 Hz), 4.12-3.92 (5H, m), 3.73 (1H, dd, J=12.8, 8.5
Hz).
MS spectrum (ES/APCI.sup.+): 494 (M+H), 496 (M+2+H)
(Example 64)
5-chloro-2-methoxy-N-[(10aS)-9-methyl-7-oxo-7,8,9,10,10a,
11-hexahydro-5H-pyrazino[2,1-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesul-
fonamide
(64a) (6S)-4-benzyl-6-(hydroxymethyl)piperazin-2-one
To a mixture of tert-butyl
(4R)-4-formyl-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (4.00 g,
17.4 mmol), ethyl N-benzylglycinate (6.42 mL, 34.9 mmol) and acetic
acid (2.00 mL, 34.9 mmol) in methanol (60 mL), sodium
cyanoborohydride (1.64 g, 26.2 mmol) was added in portion-wise
manner over 10 minutes under ice cooling, the mixture was stirred
at the same temperature as above for 30 minutes, and then stirred
at room temperature for 18 hours. Potassium carbonate was added
thereto until gas generation stopped, and the mixture was stirred
at room temperature for a while. The mixture was concentrated under
reduced pressure, diluted by addition of water (50 mL), a saturated
aqueous solution of sodium bicarbonate (50 mL) and a saturated
aqueous solution of sodium chloride (50 mL), and followed by
extraction with methylene chloride three times. The organic layers
were combined, and dried over anhydride sodium sulfate. After
filtration, the solvent was distilled off under reduced pressure,
and the residue was purified in an automatic chromatography
apparatus (n-hexane/ethyl acetate=90/10-70/30) to obtain tert-butyl
(4S)-4-{[benzyl(2-ethoxy-2-oxoethyl)amino]methyl}-2,2-dimethyl-1,3-oxazol-
idine-3-carboxylate (4.56 g, yield: 64%).
To a solution of tert-butyl
(4S)-4-{[benzyl(2-ethoxy-2-oxoethyl)amino]methyl}-2,2-dimethyl-1,3-oxazol-
idine-3-carboxylate (4.40 g, 10.8 mmol) obtained in the above step
in methanol (50 mL), a 5.0 mol/L hydrochloric acid (5 mL, 25 mmol)
was added at room temperature, and the mixture was stirred at
100.degree. C. for 26.5 hours in an oil bath. After cooling, the
mixture was concentrated under reduced pressure up to approximately
1/3 volume, and diluted by addition of a saturated aqueous solution
of sodium bicarbonate until it became weak basic, followed by
extraction with methylene chloride four times. The organic layers
were combined, and dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the residue was
purified in an automatic chromatography apparatus (methylene
chloride/methanol=100/0-90/10) to obtain the title compound (1.47
g, yield: 62%).
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 7.37-7.28 (5H, m),
6.70 (1H, br s), 3.65-3.61 (2H, m), 3.55-3.51 (2H, m), 3.41 (1H, br
s), 3.21 (1H, d, J=16.4 Hz), 3.09 (1H, d, J=16.4 Hz), 2.72 (1H, dd,
J=12.1, 4.3 Hz), 2.61 (1H, dd, J=12.1, 5.1 Hz).
(64b) tert-butyl
(3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxopiperazine-1-carboxy-
late
A mixture of (6S)-4-benzyl-6-(hydroxymethyl)piperazin-2-one (1.42
g, 6.45 mmol) obtained in Example (64a), di-tert-butyl dicarbonate
(1.69 g, 7.74 mmol) and 20% palladium hydroxide on carbon (water
content: 50%, 500 mg) in methanol (30 mL) was stirred at room
temperature for 20 hours at normal pressure under the hydrogen
atmosphere. Hydrogen in the reaction container was replaced with
nitrogen, and then, the reaction mixture was filtered through pad
of Celite 545.RTM.. The solvent in the filtrate was distilled off
under reduced pressure, the residue was purified in an automatic
chromatography apparatus (methylene chloride/methanol=100/0-95/5)
to obtain tert-butyl
(3S)-3-(hydroxymethyl)-5-oxopiperazine-1-carboxylate (1.31 g,
yield: 88%).
To a solution of tert-butyl
(3S)-3-(hydroxymethyl)-5-oxopiperazine-1-carboxylate (1.30 g, 5.65
mmol) obtained in the above step in N,N-dimethylformamide (15 mL),
imidazole (0.846 g, 12.4 mmol) and tert-butyldimethylchlorosilane
(0.936 g, 6.21 mmol) was added at room temperature, and the mixture
was stirred at the same temperature as above for 23 hours. The
mixture was concentrated under reduced pressure, diluted by
addition of a saturated aqueous solution of ammonium chloride
followed by extraction with ethyl acetate three times. The organic
layers were combined, washed with water, and dried over anhydrous
sodium sulfate. After filtration, the solvent was distilled off
under reduced pressure and the residue was purified in an automatic
chromatography apparatus (methylene chloride/methanol=100/0-97/3)
to obtain the title compound (1.91 g, yield: 98%).
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 6.26 (1H, br s),
4.23-3.55 (5H, m), 3.45 (1H, t, J=8.8 Hz), 3.23-3.10 (1H, m), 1.47
(9H, s), 0.90 (9H, s), 0.07 (6H, s).
(64c) tert-butyl
(10aS)-3-bromo-7-oxo-7,8,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[3,2-f-
][1,4]oxazepine-9(10H)-carboxylate
The title compound (396 mg, yield: 19% for 2 steps) was obtained by
production according to the method described in Examples (52c) and
(52d) using tert-butyl
(3S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxopiperazine-1-carboxy-
late (1.20 g, 3.49 mmol) obtained in Example (64b) and
(5-bromo-2-chloropyridin-3-yl)methyl methanesulfonate (1.00 g, 3.33
mmol) obtained in Example (52b) as starting materials.
.sup.1H NMR spectrum (CDCl.sub.3, 400 MHz) .delta.: 8.22 (1H, d,
J=2.3 Hz), 7.81 (1H, d, J=2.3 Hz), 5.29 (1H, d, J=15.3 Hz),
4.62-4.56 (1H, m), 4.17-4.01 (5H, m), 3.90-3.70 (2H, m), 1.45 (9H,
s).
(64d)
(10aS)-3-bromo-9-methyl-9,10,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyr-
ido[3,2-f][1,4]oxazepin-7(8H)-one
To a solution of tert-butyl
(10aS)-3-bromo-7-oxo-7,8,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[3,2-f-
][1,4]oxazepine-9(10H)-carboxylate (335 mg, 0.84 mmol) obtained in
Example (64c) in methanol (2 mL), a 4.0 mol/L solution of
hydrochloric acid in 1,4-dioxane (4 mL, 16 mmol) was added at room
temperature, and the mixture was stirred at the same temperature as
above for 3 hours. The mixture was poured into a saturated aqueous
solution of sodium bicarbonate under ice cooling, followed by
extraction with a mixed solvent of methylene chloride/methanol=5/1
six times. The organic layers were combined, and dried over
anhydride sodium sulfate. After filtration, the solvent was
distilled off under reduced pressure to obtain
(10aS)-3-bromo-9,10,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[3,2-f][1,4-
]oxazepin-7(8H)-one (201 mg, 80%).
To a solution of
(10aS)-3-bromo-9,10,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[3,2-f][1,4-
]oxazepin-7(8H)-one (158 mg, 0.53 mmol) obtained in the above step
in a mixed solvent of 1,2-dichloroethane (10 mL) and methanol (1
mL), a 37% aqueous solution of formaldehyde (0.047 mL, 2.65 mmol)
and acetic acid (0.036 mL, 0.63 mmol) was added under ice cooling
followed by addition of sodium triacetoxyborohydride (449 mg, 2.12
mmol), and the mixture was stirred at the same temperature as above
for 5 hours. The mixture was diluted by addition of a saturated
aqueous solution of sodium bicarbonate followed by extraction with
methylene chloride three times. The organic layers were combined,
and dried over anhydride sodium sulfate. After filtration, the
solvent was distilled off under reduced pressure to obtain the
title compound (159 mg, 96%).
.sup.1H NMR spectrum (CDCl3, 400 MHz) .delta.: 8.21 (1H, d, J=2.3
Hz), 7.82 (1H, d, J=2.3 Hz), 5.28 (2H, d, J=15.3 Hz), 4.49 (1H, dd,
J=12.9, 2.7 Hz), 4.10 (1H, dd, J=12.9, 6.7 Hz), 4.02-3.97 (2H, m),
3.08 (2H, s), 2.79 (1H, dd, J=12.1, 4.7 Hz), 2.66 (1H, dd, J=12.1,
5.9 Hz), 2.29 (3H, s).
(64e) 5-chloro-2-methoxy-N-[(10aS)-9-methyl-7-oxo-7,8,9,10,10a,
11-hexahydro-5H-pyrazino[2,1-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesul-
fonamide
The title compound (36 mg, yield: 28%) was obtained by production
according to the method described in Example (53g) using
(10aS)-3-bromo-9-methyl-9,10,10a,11-tetrahydro-5H-pyrazino[2,1-c]pyrido[3-
,2-f][1,4]oxazepin-7(8H)-one (90 mg, 0.29 mmol) obtained in Example
(64d) and 5-chloro-2-methoxybenzenesulfonamide (77 mg, 0.35 mmol)
obtained in Example (53f) as starting materials.
.sup.1H NMR spectrum (CD.sub.3OD, 400 MHz) .delta.: 7.81 (1H, d,
J=2.7 Hz), 7.70 (1H, d, J=2.7 Hz), 7.55-7.53 (2H, m), 7.15 (1H, d,
J=9.0 Hz), 5.12 (1H, d, J=15.3 Hz), 4.58-4.54 (1H, m), 4.22 (1H, d,
J=15.3 Hz), 4.03-4.01 (2H, m), 3.93 (3H, s), 3.14 (1H, d, J=16.8
Hz), 2.97 (1H, d, J=16.8 Hz), 2.91-2.88 (1H, m), 2.65-2.62 (1H, m),
2.30 (3H, s).
MS spectrum (ES/APCI.sup.+): 453 (M+H), 455 (M+2+H).
(Example 65) Potassium
[(5-chloro-2-methoxyphenyl)sulfonyl][(10aS)-9-methyl-7-oxo-7,8,9,10,10a,
11-hexahydro-5H-pyrazino[2,1-c]pyrido[3,2-f][1,4]oxazepin-3-yl]azanide
(Potassium Salt of Example 64)
The title compound (12.5 mg, yield: 77%) was obtained by production
according to the method described in Example 33 using
5-chloro-2-methoxy-N-[(10aS)-9-methyl-7-oxo-7,8,9,10,10a,11-hexahydro-5H--
pyrazino[2,1-c]pyrido[3,2-f][1,4]oxazepin-3-yl]benzenesulfonamide
(15 mg, 0.033 mmol) obtained in Example (64e) as a starting
material.
.sup.1H NMR spectrum (DMSO-d6, 400 MHz) .delta.: 7.64 (1H, d, J=2.7
Hz), 7.39 (1H, d, J=2.7 Hz), 7.32 (1H, dd, J=9.0, 2.7 Hz), 7.15
(1H, d, J=2.7 Hz), 6.97 (1H, d, J=9.0 Hz), 4.88 (1H, d, J=14.9 Hz),
4.38-4.31 (2H, m), 3.96 (1H, d, J=14.9 Hz), 3.86 (1H, s), 3.74 (1H,
dd, J=12.3, 6.8 Hz), 3.65 (3H, s), 2.88-2.85 (2H, m), 2.72-2.69
(1H, m), 2.16 (3H, s)
TEST EXAMPLES
(Test Example 1) Inhibitory Test of TNAP Activity
COS1 cells (DS Pharma Biomedical Co., Ltd.) were transfected with
human TNAP (OriGene Technologies, Inc.) using Lipofectamine LTX
& Plus reagent (Invitrogen Corp.). On the next day, the medium
was replaced with a fresh medium, and the cells were cultured in an
incubator for 3 days. After 3 days, the culture supernatant was
collected and concentrated by centrifugation at 5000 G for 30
minutes using Amicon 14, 10.sup.4 cut (Merck Millipore). The
concentrated culture supernatant was dialyzed against 5 L of 50 mM
Tris/200 mM NaCl/1 mM MgCl.sub.2/20 .mu.M ZnCl.sub.2 twice and used
as an enzyme source (enzyme solution). The substrate pNPP
(ProteoChem Inc.) was adjusted to 3.1 mM with Milli-Q water, and a
solution of each test compound dissolved in dimethyl sulfoxide
(DMSO; Wako Pure Chemical Industries, Ltd.) by 6 serial dilutions
at a 5-fold common ratio from 100 .mu.M, or DMSO was added thereto
at a final concentration of 1% by volume. The enzyme solution
adjusted to 2 .mu.g/mL with an assay buffer (200 mM Tris/2 mM
MgCl.sub.2/0.04 mM ZnCl.sub.2/0.01% Tween 20) was added in the same
amount of the substrate solution and incubated at room temperature
for 60 minutes. Then, the absorbance (ABS: 405 nm) was measured
using a microplate reader (model plus 384, Molecular Devices, LLC),
and the concentration of produced p-nitrophenol was calculated. The
inhibition of human TNAP activity by the test compound was
evaluated on the basis of the concentration IC.sub.50 at which each
test compound suppressed 50% of p-nitrophenol production.
The results are shown in Table 1.
TABLE-US-00001 TABLE 1 Example compound No. IC.sub.50 (nM) 1 2.6 3
2.4 5 2.8 6 5.9 7 6.5 9 3.4 11 12.6 12 8.5 13 5.1 14 3.6 16 3.5 17
6.9 18 2.8 20 4.2 21 3.0 23 5.7 24 2.3 26 29.4 27 13.2 28 1.2 29
7.1 30 0.9 31 1.2 32 0.9 34 1.6 35 0.9 36 1.5 37 1.4 39 2.4 40 5.8
41 0.4 42 0.4 44 0.8 45 2.0 46 0.5 47 1.5 48 0.6 50 0.5 52 2.2 53
4.3 54 1.1 56 1.4 58 3.8 59 1.4 60 3.3 61 0.6 63 1.4 64 1.8
The compound of the present invention exhibits the excellent
inhibition of human TNAP activity and is useful as a pharmaceutical
agent for the treatment or prophylaxis of ectopic
calcification.
(Test Example 2) Specific Inhibitory Test of TNAP Activity
COS1 cells (DS Pharma Biomedical Co., Ltd.) were transfected with
human IAP (small-intestinal alkaline phosphatase, purchased from
OriGene Technologies, Inc.) or human PLAP (placental alkaline
phosphatase, purchased from OriGene Technologies, Inc.) using
Lipofectamine LTX & Plus reagent (Invitrogen Corp.). On the
next day, the medium was replaced with a fresh medium, and the
cells were cultured in an incubator for 3 days. After 3 days, the
culture supernatant was collected and concentrated by
centrifugation at 5000 G for 30 minutes using Amicon 14, 10.sup.4
cut (Merck Millipore). The concentrated culture supernatant was
dialyzed against 5 L of 50 mM Tris/200 mM NaCl/1 mM MgCl.sub.2/20
.mu.M ZnCl.sub.2 twice and used as an enzyme source (enzyme
solution). The substrate pNPP (ProteoChem Inc.) was adjusted to 3.1
mM with Milli-Q water, and a solution of each test compound
dissolved in dimethyl sulfoxide (DMSO; Wako Pure Chemical
Industries, Ltd.) by 6 serial dilutions at a 5-fold common ratio
from 100 .mu.M, or DMSO was added thereto at a final concentration
of 1% by volume. The enzyme solution of human IAP or human PLAP
adjusted to 2 .mu.g/mL with an assay buffer (200 mM Tris/2 mM
MgCl.sub.2/0.04 mM ZnCl.sub.2/0.01% Tween 20) was added in the same
amount of the substrate solution and incubated at room temperature
for 60 minutes. Then, the absorbance (ABS: 405 nm) was measured
using a microplate reader (model plus 384, Molecular Devices, LLC),
and the concentration of produced p-nitrophenol was calculated. The
inhibition of human IAP or PLAP activity by the test compound was
evaluated on the basis of the concentration IC.sub.50 at which each
test compound suppressed 50% of p-nitrophenol production.
The compound of the present invention exhibits the excellent
specific inhibition of TNAP activity and is useful as a
pharmaceutical drug for the treatment or prevention of ectopic
calcification.
(Test Example 3) Inhibitory Test of Plasma TNAP Activity in B6
Mouse (Charles River Laboratories Japan, Inc.)
After blood sampling from the tail vein using a heparin-treated
hematocrit capillary tube (EM Meister Hematocrit Capillary Tube, AS
ONE Corp.) (as the sample before compound administration), each
test compound suspended in a 0.5% methylcellulose solution (powder
purchased from Wako Pure Chemical Industries, Ltd. was adjusted to
0.5% with Otsuka distilled water) was administered orally to the
mouse. 1, 2, 4, 6, and 24 hours after the administration, blood was
collected from the tail vein using a heparin-treated hematocrit
capillary tube to obtain a plasma sample. The plasma sample was
added to an assay buffer (1 M Tris, 1 M MgCl.sub.2, 20 mM
ZnCl.sub.2, and water, pH 7.5), and the mixture was left standing
for 5 minutes. Then, the absorbance at 405 nm was measured and used
as a blank. The substrate pNPP was added to the plasma sample and
incubated at room temperature for 180 minutes. Then, the absorbance
(ABS: 405 nm) was measured using a microplate reader (model plus
384, Molecular Devices, LLC), and the concentration of produced
p-nitrophenol was calculated. The blank was subtracted from all
measurement values to calculate TNAP activity at each time point
with the TNAP activity of the sample before compound administration
defined as 100%. The pharmaceutical effect of the test compound was
evaluated by the average inhibition of plasma ALP (80-90%
containing TNAP) activity for 6 hours from 0 hour to 6 hour after
the administration of the test compound. It was calculated
according to the following expression: 100-((plasma ALP activity at
0 hr+plasma ALP activity at 1 hr)*1/2+(plasma ALP activity at 1
hr+plasma ALP activity at 2 hr)*1/2+(plasma ALP activity at 2
hr+plasma ALP activity at 4 hr)*2/2+(plasma ALP activity at 4
hr+plasma ALP activity at 6 hr)*2/2)/6 The results are shown in
Table 2.
TABLE-US-00002 TABLE 2 Plasma ALP inhibition (6 h Example ave.
compound No. Dose (mg/kg) inhibition %) 2 1 34.4 4 1 40.7 8 3 29.4
10 3 43.3 15 3 61.4 19 3 27.5 22 3 28.4 25 3 55.5 33 0.3 59.0 38
0.3 65.5 43 0.3 65.5 49 1 52.8 51 1 59.7 55 1 65.7 62 1 76.0
The compound of the present invention exhibits an excellent in vivo
TNAP inhibitory effect and is useful as a pharmaceutical agent for
the treatment or prophylaxis of ectopic calcification.
(Test Example 4) In Vivo Anti-Calcification Test in Vitamin
D-Induced Calcification Model
A DBA/2 mouse (male, 6 weeks old when used, Charles River
Laboratories Japan, Inc.) is given powder feed (FR-2 powder feed,
Funabashi Farm Co., Ltd.) containing each test compound. 3.75 mg/kg
cholecalciferol (Sigma-Aldrich Corp.) is intraperitoneally
administered for 3 days from the next day. Seven days after the
final cholecalciferol administration, the animal is sacrificed, and
the thoracic aorta and the kidney are sampled. The tissue samples
are freeze-dried (FREEZE DRYER, FRD-50M, Iwaki Asahi Techno Glass
Corp.). Then, 10% formic acid (undiluted solution purchased from
Kishida Chemical Co., Ltd. is adjusted to 10% with Milli-Q water)
is added to each tissue sample, which is then homogenized using
QIAGEN Retsch MM300 TissueLyser (Qiagen N. V.). The homogenate is
centrifuged, and the supernatant is used as a sample. The calcium
concentration in the sample is measured as absorbance (ABS 612 nm,
Microplate reader, model plus 384, Molecular Devices, LLC) using
Calcium assay kit (Wako Pure Chemical Industries, Ltd.) to
calculate the amount of calcium in the tissue.
The compound of the present invention exhibits an excellent
anti-calcification effect and is useful as a therapeutic agent for
the treatment or prevention of ectopic calcification.
(Test Example 5) In Vivo Anti-Calcification Test in Nephrectomized
Mouse
A 5/6 nephrectomized DBA/2 mouse (male, 8 weeks old) is purchased
from CLEA Japan, Inc. This mouse is loaded with 1.2%
high-phosphorus diet (Oriental Yeast Co., Ltd.). Each test compound
suspended in a 0.5% methylcellulose solution (powder purchased from
Wako Pure Chemical Industries, Ltd. is adjusted to 0.5% with Otsuka
distilled water) is administered orally twice daily for three
months. After three months, the animal is sacrificed, and the
kidney is sampled. The tissue sample is freeze-dried (FREEZE DRYER,
FRD-50M, Iwaki Asahi Techno Glass Corp.). Then, 10% formic acid
(undiluted solution purchased from Kishida Chemical Co., Ltd. is
adjusted to 10% with Milli-Q water) is added to the tissue sample,
which is then homogenized using QIAGEN Retsch MM300 TissueLyser
(Qiagen N. V.). The homogenate is centrifuged, and the supernatant
is used as a sample. The calcium concentration in the sample is
measured as absorbance (ABS 612 nm, Microplate reader, model plus
384, Molecular Devices, LLC) using Calcium assay kit (Wako Pure
Chemical Industries, Ltd.) to calculate the amount of calcium in
the tissue.
The compound of the present invention exhibits an excellent
anti-calcification effect and is useful as a pharmaceutical drug
for the treatment or prophylaxis of ectopic calcification.
(Test Example 6) Pharmacokinetic Test
The pharmacokinetic test can be conducted according to a method
well-known in the field of pharmacodynamics.
Each test compound was suspended in a 0.5% aqueous methylcellulose
solution. The obtained suspension was orally administered at a dose
in an appropriate range (e.g., 0.01 mg/kg to 10 mg/kg) to an animal
(e.g., a mouse, a rat, a dog, or a cynomolgus monkey) generally
used in the pharmacokinetic test. Also, the test compound was
dissolved in saline. The obtained solution was intravenously (e.g.,
through the tail vein, the cephalic vein, or the saphenous vein)
administered at a dose in an appropriate range (e.g., 0.1 mg/kg to
10 mg/kg) to an animal (e.g., a mouse, a rat, a dog, or a
cynomolgus monkey) generally used in the pharmacokinetic test.
After given times (e.g., 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24
hours) from the administration, blood was collected from an
appropriate blood collection site (e.g., the jugular vein, the
cephalic vein, or the saphenous vein). The obtained blood was
centrifuged to prepare a plasma sample. The concentration of the
test compound contained in the plasma sample was measured by
quantitative analysis using a liquid chromatography-mass
spectrometer (LC-MS/MS).
The pharmacokinetics of the test compound were evaluated on the
basis of maximum plasma concentration (Cmax), area under the plasma
drug concentration-time curve (AUC), total clearance (CL), and
bioavailability and analyzed using software (Phoenix, etc.). Cmax
represents the maximum plasma concentration of the orally
administered test compound. AUC was calculated according to the
trapezium rule from the plasma concentrations of the test compound
from the time when the test compound was administered up to the
final time when the test compound was quantifiable. The
bioavailability was calculated according to the following
expression: [(AUC after oral administration/Dose of the oral
administration)/(AUC after intravenous administration/Dose of the
intravenous administration)].
The compound of the present invention exhibits excellent
pharmacokinetics (Cmax, AUC, CL, or bioavailability) and is useful
as a pharmaceutical (particularly, a pharmaceutical for the
treatment or prevention of ectopic calcification).
PREPARATION EXAMPLES
TABLE-US-00003 (Preparation Example 1) Capsule Compound of Example
1 50 mg Lactose 128 mg Corn starch 70 mg Magnesium stearate 2 mg
250 mg
A powder having the formulation mentioned above is mixed and sifted
through a 60-mesh sieve. Then, this powder is put in a gelatin
capsule shell to prepare a capsule.
TABLE-US-00004 (Preparation Example 2) Tablet Compound of Example 1
50 mg Lactose 126 mg Corn starch 23 mg Magnesium stearate 1 mg 200
mg
A powder having the formulation mentioned above is mixed,
granulated using corn starch paste, and dried, followed by
compression in a tableting machine to prepare tablets (200 mg
each). This tablet can be coated, if necessary.
The novel pyridine compound represented by the general formula (I)
of the present invention or the pharmacologically acceptable salt
thereof has an excellent TNAP inhibitory effect and is useful as a
pharmaceutical.
* * * * *